US8232265B2 - Multi-functional ionic liquid compositions for overcoming polymorphism and imparting improved properties for active pharmaceutical, biological, nutritional, and energetic ingredients - Google Patents

Multi-functional ionic liquid compositions for overcoming polymorphism and imparting improved properties for active pharmaceutical, biological, nutritional, and energetic ingredients Download PDF

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US8232265B2
US8232265B2 US11/545,938 US54593806A US8232265B2 US 8232265 B2 US8232265 B2 US 8232265B2 US 54593806 A US54593806 A US 54593806A US 8232265 B2 US8232265 B2 US 8232265B2
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hydrochloride
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disclosed
function
ionic liquid
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US20070093462A1 (en
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Robin D. Rogers
Daniel T. Daly
Richard P. Swatloski
Whitney L. Hough
James Hilliard Davis, Jr.
Marcin Smiglak
Juliusz Pernak
Scott K. Spear
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University of Alabama at Birmingham
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
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Definitions

  • the subject matter disclosed herein generally relates to ionic liquids and to methods of preparing ionic liquid compositions of active pharmaceutical, biological, nutritional, and energetic ingredients. Also the subject matter disclosed herein generally relates to methods of using the compositions described herein to overcome polymorphism, overcome solubility and delivery problems, to control release rates, add functionality, enhance efficacy (synergy), and improve ease of use and manufacture.
  • Polymorphism is the ability of a substance to exist in two or more crystalline forms that have a different arrangement and/or conformation of molecules in a crystalline lattice (see e.g., Chawla and Bansal, CRIPS 2004, 5(1):9-12; Bernstein, “Polymorphism in Molecular Crystals,” IUCR Monographs on Crystallography 14, Oxford Science Publications, 2002, pp. 1-28, 240-256). It has been estimated that a large number of pharmaceuticals exhibit polymorphism.
  • solvent molecules may become entrapped or bound within the crystal lattice.
  • the presence of the entrapped solvent molecules may affect the three-dimensional crystal lattice that eventually crystallizes.
  • pseudo-polymorphism The occurrence of a compound (target molecule) crystallizing in different three-dimensional lattices based upon the presence of solvent molecules has been termed “pseudo-polymorphism.”
  • stoichiometric i.e., whole number ratios of target molecules to solvent molecules
  • non-stoichiometric i.e., non-whole number ratios of target molecules to solvent molecules
  • the Cambridge Structural Database (Allen, “The Cambridge Structural Database: a quarter of a million crystal structures and rising,” Acta Crystallographica, 2002, B58, 380-388) is a database of over 300,000 organic crystal structures and is a widely used reference source in crystallography.
  • One survey of the Cambridge Structural Database shows that pharmaceutical compounds have been reported to exist as hemi-hydrates (0.5 water molecules) through decahydrates (10 water molecules).
  • decahydrates (10 water molecules).
  • polymorphism or pseudo-polymorphism may exist for any particular compound, but the conditions required to prepare as yet unknown polymorphs or pseudo-polymorphs are not easily determined (see e.g., Bernstein, “Crystal Structure Prediction and Polymorphism,” Am Crystallographic Assoc Trans, 2004, 39:14-23).
  • polymorphs or pseudo-polymorphs can greatly affect a pharmaceutical's performance since each form can have different physical and chemical properties.
  • one particular polymorph pseudo-polymorph may be more bioavailable, more stable (e.g., longer shelf life), or more easily formulated or tableted than another polymorph.
  • one polymorph pseudo-polymorph may be more active or less toxic than another.
  • the effects of polymorphism and pseudo-polymorphism on quality and performance of a drug is widely recognized.
  • the exact solid state polymorph (or pseudo-polymorph) of a compound determines its physical properties such as dissolution rate, solubility, bioavailability, crystal habit, mechanical strength, etc. (Datta et al., Nature Reviews - Drug Discovery, 2004, 3:42-57).
  • the delivery of an exact dosage in manufacture and the manufacturing process itself often depend on which of several possible polymorphs or pseudo-polymorphs are present.
  • the variation in properties among different polymorphs usually means that one crystalline form is desired or preferred over other forms. Obtaining a particular form can be difficult, however. Typically, researchers have to experiment with a multitude of variables in crystallization conditions, such as aqueous solvent mixtures, amount of water, amount of target compound, relative humidity, temperature of incubation, incubation time, etc., in a process characterized by trial and error. Further, the search for salts of crystalline forms (usually sought after to control dissolution rate and solubility) can require extensive experimentation.
  • Each salt of a drug or each different solvent used to crystallize the drug or a salt of the drug may lead to polymorphs or pseudo-polymorphs that have to be fully investigated and that have different properties (see e.g., Reutzel-Edens et al., “Anhydrates and hydrates of olanzapine: Crystallization, solid-state characterization, and structural relationships,” Crystal Growth & Design, 2003, 3:897-907).
  • Amorphous forms of drugs are now being studied because they are higher energy forms that have higher dissolution rates and solubilities since there is no lattice structure to overcome or to inhibit solvation (Bernstein, “Polymorphism in Molecular Crystals,” IUCR Monographs on Crystallography 14, Oxford Science Publications, 2002, pp. 240-256). This increasing attention to amorphous forms has also shown, however, that the amorphous forms have a tendency to crystallize spontaneously to a lower energy crystalline form, usually at inopportune times.
  • the phenomenon of polymorphism and pseudo-polymorphism is not limited to pharmaceuticals as many other (if not all) organic and inorganic compounds can crystallize into different forms.
  • a given compound e.g., a pesticide, herbicide, nutraceutical, cosmetic, food additive, explosive, etc.
  • polymorphic and pseudo-polymorphic drugs can result in the same synthetic, analytical, regulatory, and commercial difficulties that plague the pharmaceutical industry because of polymorphic and pseudo-polymorphic drugs.
  • compositions that are at least effective for their intended purpose, but can also have controlled and tunable chemical, biological, and physical properties, are in a form that is not subject to polymorphism, and for which controlled, tunable dissolution and solubility are possible. Methods of preparing and using such compositions are also needed. Further methods of converting a compound that is difficult to solubilize into a more soluble form are also desired.
  • the compositions and methods disclosed herein meet these and other needs including the introduction of enhanced or new functionality.
  • the disclosed subject matter in one aspect, relates to compounds and compositions and methods for preparing and using such compounds and compositions.
  • the disclosed subject matter relates to ionic liquid compositions that can be used for or in biological, pharmaceutical, nutritional, cosmetic, industrial, and commercial compositions. Methods for making the disclosed ionic liquid compositions are also disclosed. Also disclosed are methods of preparing ionic liquid compositions of active pharmaceutical, biological, nutritional, and energetic ingredients. Also the disclosed are methods of using the compositions described herein to overcome polymorphism, overcome solubility and delivery problems, to control release rates, add functionality, enhance efficacy (synergy), and improve ease of use and manufacture.
  • FIG. 1 is a graph of absorbance at 258 nanometers (nm) over time (minutes) for hexadecylpyridinium sulfacetamide ([Hex] sulfacetamide), hexadecylpyridinium chloride ([Hex][Cl]), and sodium sulfacetamide dissolution.
  • FIG. 2 is a graph of absorbance at 258 nm over time for hexadecylpyridinium sulfacetamide and didecyldimethylammonium (DDA) sulfacetamide dissolution.
  • DDA didecyldimethylammonium
  • FIG. 3 is a schematic of a computer model used to identify ion combinations suitable for the disclosed ionic liquid combinations.
  • FIG. 4A is a graph showing a comparison of lidocaine hydrochloride and lidocaine docusate at Imillmolar concentration.
  • FIG. 4B is a graph showing a comparison of lidocaine hydrochloride and lidocaine docusate at 100 millimolar concentration.
  • FIG. 5 is a graph showing molar conductivity for [C 4 mim]Cl solutions at variable temperature; (•) 291.0 K; ( ⁇ ) 295.3 K; ( ⁇ ) 300.2 K; ( ⁇ ) 305.0 K in water and ( ⁇ ) in DMSO at 295.3 K.
  • FIG. 6 is a graph showing the difference in calculated limiting slope and actually measured ( ⁇ ) [C 4 mim]Cl in H 2 O at 295.3 K; ( ⁇ ) [C 4 mim]Cl in DMSO at 295.3 K.
  • Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed.
  • a “subject” is meant an individual.
  • the “subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.), and birds.
  • “Subject” can also include a mammal, such as a primate or a human.
  • reduce or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g., microorganism growth or survival). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces bacteria growth” means lowering the amount of bacteria relative to a standard or a control.
  • prevent or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed.
  • treat or other forms of the word, such as “treated” or “treatment,” is meant to administer a composition or to perform a method in order to reduce, prevent, inhibit, break-down, or eliminate a particular characteristic or event (e.g., microorganism growth or survival).
  • control is used synonymously with the term “treat.”
  • antibacterial is meant the ability to treat or control (e.g., reduce, prevent, inhibit, break-down, or eliminate) microorganism growth or survival at any concentration.
  • antibacterial e.g., reduce, prevent, inhibit, break-down, or eliminate
  • antifungal respectively mean the ability to treat or control (e.g., reduce, prevent, inhibit, break-down, or eliminate) bacterial, viral, and flmgal growth or survival at any concentration.
  • references in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which the component is included.
  • the term “ion,” as used herein, refers to any molecule, portion of a molecule, cluster of molecules, molecular complex, moiety, or atom that contains a charge (positive, negative, or both (e.g., zwitterions)) or that can be made to contain a charge.
  • Methods for producing a charge in a molecule, portion of a molecule, cluster of molecules, molecular complex, moiety, or atom are disclosed herein and can be accomplished by methods known in the art, e.g., protonation, deprotonation, oxidation, reduction, alkylation, etc.
  • anion is a type of ion and is included within the meaning of the term “ion.”
  • An “anion” is any molecule, portion of a molecule (e.g., Zwitterion), cluster of molecules, molecular complex, moiety, or atom that contains a net negative charge or that can be made to contain a net negative charge.
  • anion precursor is used herein to specifically refer to a molecule that can be converted to an anion via a chemical reaction (e.g., deprotonation).
  • cation is a type of ion and is included within the meaning of the term “ion.”
  • a “cation” is any molecule, portion of a molecule (e.g., Zwitterion), cluster of molecules, molecular complex, moiety, or atom, that contains a net positive charge or that can be made to contain a net positive charge.
  • cation precursor is used herein to specifically refer to a molecule that can be converted to a cation via a chemical reaction (e.g., protonation or alkylation).
  • the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms, such as nitrogen can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • substitution or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • a 1 ,” “A 2 ,” “A 3 ,” and “A 4 ” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
  • aliphatic refers to a non-aromatic hydrocarbon group and includes branched and unbranched, alkyl, alkenyl, or alkynyl groups.
  • alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group can also be substituted or unsubstituted.
  • the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.
  • groups including, but not limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below
  • alkyl is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group.
  • halogenated alkyl specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
  • alkylamino specifically refers to an alkyl group that is substituted with one or more amino groups, as described below, and the like.
  • alkyl is used in one instance and a specific term such as “alkylalcohol” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “alkylalcohol” and the like.
  • cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties
  • the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.”
  • a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy”
  • a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like.
  • the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.
  • alkoxy as used herein is an alkyl group bound through a single, terminal ether linkage; that is, an “alkoxy” group can be defined as —OA 1 where A 1 is alkyl as defined above.
  • alkenyl as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond.
  • Asymmetric structures such as (A 1 A 2 )C ⁇ C(A 3 A 4 ) are intended to include both the E and Z isomers. This may be presumed in structural formulae herein wherein an asymmetric alkene is present, or it may be explicitly indicated by the bond symbol C ⁇ C.
  • the alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.
  • groups including, but not limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described
  • alkynyl as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond.
  • the alkynyl group can be substituted with one or more groups including, but not limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.
  • aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like.
  • aryl also includes “heteroaryl,” which is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus.
  • non-heteroaryl which is also included in the term “aryl,” defines a group that contains an aromatic group that does not contain a heteroatom. The aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein.
  • the term “biaryl” is a specific type of aryl group and is included in the definition of aryl. Biaryl refers to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
  • cycloalkyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • heterocycloalkyl is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • the cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein.
  • cycloalkenyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one double bound, i.e., C ⁇ C.
  • cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.
  • heterocycloalkenyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein.
  • cyclic group is used herein to refer to either aryl groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups), or both. Cyclic groups have one or more ring systems that can be substituted or unsubstituted. A cyclic group can contain one or more aryl groups, one or more non-aryl groups, or one or more aryl groups and one or more non-aryl groups.
  • aldehyde as used herein is represented by the formula —C(O)H. Throughout this specification “C(O)” is a short hand notation for C ⁇ O.
  • amine or “amino” as used herein are represented by the formula NA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • carboxylic acid as used herein is represented by the formula —C(O)OH.
  • a “carboxylate” as used herein is represented by the formula —C(O)O ⁇ .
  • esters as used herein is represented by the formula —OC(O)A 1 or —C(O)OA 1 , where A 1 can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • ether as used herein is represented by the formula A 1 OA 2 , where A 1 and A 2 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • ketone as used herein is represented by the formula A 1 C(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • halide refers to the halogens fluorine, chlorine, bromine, and iodine.
  • hydroxyl as used herein is represented by the formula —OH.
  • nitro as used herein is represented by the formula —NO 2 .
  • sil as used herein is represented by the formula —SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • sulfo-oxo is represented by the formulas —S(O)A 1 , —S(O) 2 A 1 , —OS(O) 2 A 1 , or —OS(O) 2 OA 1 , where A 1 can be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • S(O) is a short hand notation for S ⁇ O.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula —S(O) 2 A 1 , where A 1 can be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • sulfonylamino or “sulfonamide” as used herein is represented by the formula —S(O) 2 NH—.
  • a 1 S(O) 2 A 2 is represented by the formula A 1 S(O) 2 A 2 , where A 1 and A 2 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • sulfoxide as used herein is represented by the formula A 1 S(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • thiol as used herein is represented by the formula —SH.
  • R 1 ,” “R 2 ,” “R 3 ,” “R n ,” etc., where n is some integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an amine group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
  • an alkyl group comprising an amino group the amino group can be incorporated within the backbone of the alkyl group.
  • the amino group can be attached to the backbone of the alkyl group.
  • the nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • bioactive property is any local or systemic biological, physiological, or therapeutic effect in a biological system.
  • the bioactive property can be the control of infection or inflammation, enhancement or suppression of growth, action as an analgesic, anti-viral, pesticidal, herbicidal, or nutrientional action, etc.
  • bioactive properties are disclosed herein.
  • the term “energetic” is used to described a compound having a heat of combustion of greater than about 500 kcal/mol (e.g., about 750, 1000, 1500 kcal/mol or more).
  • a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture.
  • Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art.
  • the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), Sigma (St.
  • ionic liquid compositions In one aspect, disclosed herein are ionic liquid compositions.
  • the term “ionic liquid” has many definitions in the art, but is used herein to refer to salts (i.e., compositions comprising cations and anions) that are liquid at a temperature of at or below about 150° C. That is, at one or more temperature ranges or points at or below about 150° C. the disclosed ionic liquid compositions are liquid; although, it is understood that they can be solids at other temperature ranges or points. Since the disclosed ionic liquid compositions are liquid, and thus not crystalline solids, at a given temperature, the disclosed compositions do not suffer from the problems of polymorphism associated with crystalline solids.
  • liquid to describe the disclosed ionic liquid compositions is meant to describe a generally amorphous, non-crystalline, or semi-crystalline state.
  • the disclosed ionic liquid compositions have minor amounts of such ordered structures and are therefore not crystalline solids.
  • the compositions disclosed herein can be fluid and free-flowing liquids or amorphous solids such as glasses or waxes at a temperature at or below about 150° C.
  • the disclosed ionic liquid compositions are liquid at the body temperature of a subject.
  • the disclosed ionic liquid compositions are materials composed of at least two different ions; each of which can independently and simultaneously introduce a specific characteristic to the composition not easily obtainable with traditional dissolution and formulation techniques.
  • characteristics that can be controlled in the disclosed compositions include, but are not limited to, melting, solubility control, and rate of dissolution. It is this multi-nature/functionality of the disclosed ionic liquid compositions which allows one to fine-tune or design in very specific desired material properties.
  • the disclosed ionic liquid compositions can include solvent molecules (e.g., water); however, these solvent molecules should not be present in excess in the sense that the disclosed ionic liquid compositions are dissolved in the solvent, forming a solution. That is, the disclosed ionic liquid compositions contain no or minimal amounts of solvent molecules that are free and not bound or associated with the ions present in the ionic liquid composition. Thus, the disclosed ionic liquid compositions can be liquid hydrates or solvates, but not solutions.
  • solvent molecules e.g., water
  • Ionic liquids have been of general interest because they are environmentally-friendly alternatives to organic solvents for various chemical processes, e.g., liquid/liquid extractions, catalysis, separations, and electrochemistry. Ionic liquids have also become popular alternative media for chemical synthesis because of their low volatility and low toxicity. See e.g., Wasserscheid and Keim, Angew Chem Int Ed Engl, 2000, 39:3772; and Wasserscheid, “Ionic Liquids in Synthesis,” 1 st Ed., Wiley-VCH, 2002. Further, ionic liquids can reduce costs, disposal requirements, and hazards associated with volatile organic compounds.
  • exemplary properties of ionic liquids are high ionic conductivity, non-volatility, non-flammability, high thermal stability, wide temperature for liquid phase, highly solvability, and non-coordinating.
  • ionic liquids see, for example, Welton, Chem Rev. 1999, 99:2071-2083; and Carlin et al., Advances in Nonaqueous Chemistry, Mamantov et al. Eds., VCH Publishing, New York, 1994.
  • the specific physical properties (e.g., melting point, viscosity, density, water solubility, etc.) of ionic liquids are determined by the choice of cation and anion, as is disclosed more fully herein.
  • the melting point for an ionic liquid can be changed by making structural modifications to the ions or by combining different ions.
  • the particular chemical properties e.g., bioactivity, toxicity, pharmacokinetics, etc.
  • the ionic liquid compositions disclosed herein are comprised of at least one kind of anion and at least one kind of cation.
  • the at least one kind of cation, the at least one kind of anion, or both can be a pharmaceutical active, a pesticidal active, a herbicidal active, a food additive, a nutraceutical, or the like, including any combination thereof, as is disclosed herein.
  • the disclosed ionic liquid compositions can comprise one kind of cation with more than one kind of anion (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different kinds of anions).
  • the disclosed ionic liquid compositions can comprise one kind of anion with more than one kind of cation (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different kinds of cations). Further, the disclosed ionic liquids can comprise more than one kind of anion (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different kinds of anions) with more than one kind of cation (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different kinds of cations).
  • Specific examples include, but are not limited to, one kind of cation with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 2 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 3 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 4 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 5 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 6 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 7 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 8 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 9 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 10 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, or more than 10
  • the ionic liquid compositions disclosed herein can also contain nonionic species, such as solvents, preservatives, dyes, colorants, thickeners, surfactants, viscosity modifiers, mixtures and combinations thereof and the like.
  • nonionic species such as solvents, preservatives, dyes, colorants, thickeners, surfactants, viscosity modifiers, mixtures and combinations thereof and the like.
  • the amount of such nonionic species is typically low (e.g., less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 wt. % based on the total weight of the composition).
  • the disclosed ionic liquid compositions are neat; that is, the only materials present in the disclosed ionic liquids are the cations and anions that make up the ionic liquid compositions.
  • the disclosed ionic liquid compositions are liquid at some temperature range or point at or below about 150° C.
  • the disclosed ionic liquids can be a liquid at or below about 150, 149, 148, 147, 146, 145, 144, 143, 142, 141, 140, 139, 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, 117, 116, 115, 114, 113, 112, 111, 110, 109, 108, 107, 106, 105, 104, 103, 102, 101, 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75,
  • the disclosed ionic liquids can be liquid at any point from about ⁇ 30° C. to about 150° C., from about ⁇ 20° C. to about 140° C., ⁇ 10° C. to about 130° C., from about 0° C. to about 120° C., from about 10° C. to about 110° C., from about 20° C. to about 100° C., from about 30° C. to about 90° C., from about 40° C. to about 80° C., from about 50° C. to about 70° C., from about ⁇ 30° C. to about 50° C., from about ⁇ 30° C. to about 90° C., from about ⁇ 30° C. to about 110° C., from about ⁇ 30° C.
  • the disclosed ionic liquid compositions can be liquid over a wide range of temperatures, not just a narrow range of, say, 1-2 degrees.
  • the disclosed ionic liquid compositions can be liquids over a range of at least about 4, 5, 6, 7, 8, 9, 10, or more degrees.
  • the disclosed ionic liquid compositions can be liquid over at least about a 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more degree temperature range. Such temperature ranges can begin and/or end at any of the temperature points disclosed in the preceding paragraph.
  • the disclosed ionic liquid compositions are liquid at the temperature at which they will be used or processed.
  • many of the disclosed ionic liquid compositions can be used for therapeutic or nutritional purposes in a subject.
  • the disclosed ionic liquid compositions can be liquid at the subject's body temperature (e.g., about 37° C. for a human).
  • Other examples include compositions that can be used as herbicides or pesticides, which are liquid at the temperature of their use (e.g., ambient temperature).
  • the disclosed compositions can be liquid at the temperature at which they are formulated or processed.
  • the disclosed ionic liquid compositions can, though need not, be solubilized, and solutions of the disclosed ionic liquids are contemplated herein.
  • the disclosed ionic liquid compositions can be formulated in an extended or controlled release vehicle, for example, by encapsulating the ionic liquids in microspheres or microcapsules using methods known in the art.
  • the disclosed ionic liquid compositions can themselves be solvents for other solutes.
  • the disclosed ionic liquids can be used to dissolve a particular nonionic or ionic pharmaceutical active.
  • the disclosed ionic liquids are not solutions where ions are dissolved in a solute.
  • the disclosed ionic liquid compositions do not contain ionic exchange resins.
  • the disclosed ionic liquids are substantially free of water. By substantially free is meant that water is present at less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.25, or 0.1 wt. %, based on the total weight of the composition.
  • the disclosed ionic liquid compositions can be prepared by methods described herein. Generally, the particular cation(s) and anion(s) used to prepare the disclosed ionic liquids are selected as described herein. Then, with the particular cation(s) and anion(s) in hand, they can be combined, resulting in ionic liquid compositions as disclosed herein.
  • the method for the preparation of the disclosed ionic liquid compositions can include the reaction in which two neutral species: an anion precursor (e.g., in the form of an inorganic acid, carboxylic organic acid, non-carboxylic acid, or Zwitterion species) and a cation precursor (e.g., inorganic base, organic base, Zwitterion species) are combined resulting in ionic liquid compositions as disclosed herein.
  • an anion precursor e.g., in the form of an inorganic acid, carboxylic organic acid, non-carboxylic acid, or Zwitterion species
  • a cation precursor e.g., inorganic base, organic base, Zwitterion species
  • Providing ions used to prepare the disclosed ionic liquids depends, in one aspect, on the desired properties of the resulting ionic liquid composition.
  • the disclosed ionic liquid compositions can have multiple desired properties, which, at least in part, come from the properties of the cation(s) and/or anion(s) used to prepare the ionic liquid.
  • one or more kinds of cations with a desired property(ies) are provided.
  • One or more kinds of anions with a desired property(ies) that is similar or different to that of the cation(s) can likewise be provided.
  • providing a desired anion(s) and cation(s) can be done in any order, depending on the preference and aims of the practitioner. For example, a particular cation(s) can be provided and then a particular anion(s) can be provided. Alternatively, a particular anion(s) can be provided and then a particular cation(s) can be provided. Further, the cation(s) and anion(s) can be provided simultaneously.
  • providing a suitable ion can be based on selecting an ion that possesses a property that is desired (e.g., the ion has a property that is desired to be possessed by the resulting ionic liquid).
  • properties that could be desired in a suitable cation and/or anion (and thus the ionic liquid made therefrom) include, but are not limited to, biological, therapeutic, prophylactic, nutritional, pesticidal, and/or herbicidal activity. Inertness, taste, viscosity modulation, solubility modulation, stability, and toxicity are other properties of a given ion that could be desired and considered. While more specific properties are disclosed elsewhere herein, the disclosed methods and compositions are not limited to any particular combination of properties, as such will depend on the preferences and goals of the practitioner.
  • the desired properties of the cation(s) and anion(s) will be different or complimentary to one another.
  • the resulting ionic liquid can possess multiple desired properties: those properties imparted by the cation(s) and those imparted by the anion(s).
  • some or all of the ions present in the disclosed ionic liquids can independently and simultaneously introduce a specific functionality or property to the disclosed ionic liquid compositions. It is this multiple functionality characteristic that can allow one to fine-tune or design very specific physical, chemical, and bioactive properties in the disclosed ionic liquid compositions.
  • Additional functionality can be obtained by using the disclosed ionic liquid compositions as solvents to dissolve a solute(s) with another desired property, thus resulting in a solution where the ions of the ionic liquid as well as the solute contribute desired properties to the composition.
  • ions of the ionic liquid as well as the solute contribute desired properties to the composition.
  • General and specific examples of various combinations of ions and their associated properties are disclosed herein.
  • one or more ions in the disclosed ionic liquid composition can be a pharmaceutical active, e.g., an existing drug that is ionic or that can be made ionic.
  • a pharmaceutical active e.g., an existing drug that is ionic or that can be made ionic.
  • Such drugs can possess any therapeutic or prophylactic activity, many of which are described herein.
  • Combining such drugs with other ions to prepare an ionic liquid can result in the modification and/or enhancement of the drug's properties.
  • a first drug ion with a given property can be combined with an oppositely charged second ion with another property to effect the controlled release, controlled delivery, biological impact, taste, physical properties (stability, solubility, toxicity, melting point, etc.), or to overcome polymorphism in the first drug ion.
  • new drug compositions can be created by forming ionic liquids with functionality crafted into the combination of the ions, as disclosed herein.
  • the first drug ion may be combined with a second drug ion that has properties complimentary to the first.
  • this can include, but are not limited to, an ion having anesthetic properties being combined with an ion having antibacterial properties, an ion having anesthetic properties being combined with an ion having coagulation properties, or an ion having coagulation properties being combined with an ion having antibacterial properties.
  • Ionic liquids resulting from such combinations could find uses in wound repair, for example.
  • Still other examples of desirable combination include ions having therapeutic or prophylactic efficacy being combined with ions having taste enhancement properties (i.e., taste modifiers). Ionic liquids resulting from this combination can be useful in enhancing the taste and palatability of medicines.
  • Still further examples can include two differently charged ions each with similar uses but with different mechanisms of action.
  • Specific examples of such combinations can include, but are not limited to, combinations of ions with antineoplastic properties or antiviral properties.
  • Ionic liquids prepared from such ion combinations can be useful as drug “cocktails,” where two or more bioactive agents are present in a single ionic liquid combination.
  • ion identification and combination can involve any ion, not just ionic drugs, as long as the combination results in an ionic liquid.
  • ions that have pesticidal properties can be combined with oppositely charged ions having pesticidal, herbicidal, antimicrobial properties, and the like.
  • ions with antibacterial properties can be combined with oppositely charges ions that have preservative properties, taste modifiers, etc.
  • an ion with one therapeutic or prophylactic property can be combined with another therapeutic or prophylactic ion.
  • the various combinations of ions according to the disclosed methods are numerous, and depend only on the desired combination of properties and whether the resulting ion combination is an ionic liquid as defined herein.
  • compositions include antibacterial, FDA approved dyes, anti-acne, antibiotic, UV blocker, wetting agents, preservative, emollient, anti-inflammatory, and vitamin.
  • the disclosed ionic liquids contain at least one kind of cation and at least one kind of anion.
  • suitable cations and anions are disclosed herein. It should be understood that when a particular compound is disclosed as being a cation, for example, it can also, in other circumstances, be an anion and vice versa.
  • Many compounds are known to exist as cations in some environments and anions in other environments. Further, many compounds are known to be convertible to cations and anions through various chemical transformations. Examples of such compounds are disclosed herein.
  • each of the ionic liquids A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example ionic liquid A-D.
  • any subset or combination of these is also specifically contemplated and disclosed.
  • the sub-group of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D.
  • This concept applies to all aspects of this disclosure including, but not limited to, steps in methods of making and using the disclosed compositions.
  • steps in methods of making and using the disclosed compositions are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific aspect or combination of aspects of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.
  • Nitrogen atoms can exist or can be converted to positively-charged quaternary ammonium species, for example, through alkylation or protonation of the nitrogen atom.
  • compounds that possess a quaternary nitrogen atom are typically cations.
  • any compound that contains a quaternary nitrogen atom or a nitrogen atom that can be converted into a quaternary nitrogen atom can be a suitable cation for the disclosed ionic liquid compositions.
  • QACs can have numerous biological properties that one may desire to be present in the disclosed ionic liquid compositions.
  • many QACs are known to have antibacterial properties.
  • the antibacterial properties of QACs were first observed toward the end of the 19 th century among the carbonium dyestuffs, such as auramin, methyl violet, and malachite green. These types of compounds are effective chiefly against the Gram-positive organisms.
  • Jacobs and Heidelberger first discovered QACs antibacterial effect in 1915 studying the antibacterial activity of substituted hexamethylene-tetrammonium salts (Jacobs and Heidelberger, Proc Nat Acad Sci USA, 1915, 1:226; Jacobs and Heidelberger, J Biol Chem, 1915, 20:659; Jacobs and Heidelberger, J Exptl Med, 1916, 23:569).
  • Browning et al. found great and somewhat less selective bactericidal powers among quaternary derivatives of pyridine, quinoline, and phenazine (Browning et al., Proc Roy Soc London, 1922, 93B:329; Browning et al., Proc Roy Soc London, 1926, 100B:293).
  • Hartman and Kagi observed antibacterial activity in QACs of acylated alkylene diamines (Hartman and Kagi, Z Angew Chem, 1928, 4:127).
  • QACs are also widely used as skin antiseptics, disinfectants, fabric softeners, antistatic agents, cleaning agents, and preservatives. Detergent properties and antimicrobial activities of QACs have made them useful for general environmental sanitations, for examples, in hospitals and food production facilities. In pharmacological preparations they are used such as mouth rinses, lozenges, sprays and gels.
  • QACs have been considered too toxic for systematic applications, but are accepted to be safe for topical applications.
  • QACs have recently been used as penetration enhancers for transnasal and transbuccal drug delivery, as well as in nasal vaccination (Klinguer et al., Vaccine, 2001, 19:4236).
  • This ability to penetrate and open cell membrane has been widely used in drug delivery via liposomes (mainly QACs with two long alkyl chains) and non-viral gene delivery (Liu and Huang, J Contr Rel, 2002, 78:259).
  • Many examples of compounds having nitrogen atoms, which exist as quaternary ammonium species or can be converted into quaternary ammonium species, are disclosed herein.
  • the anion when the cation is a quaternary ammonium compound, the anion is not an inorganic anion, examples of which are disclosed herein. In other examples, where the cation is a quaternary ammonium compound, the anion is not a halide.
  • An aliphatic heteroaryl cation is a compound that comprises an aliphatic moiety bonded to a heteroaryl moiety.
  • the aliphatic moiety can be any alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl group, as described herein.
  • the aliphatic moiety can comprise at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20 carbon atoms.
  • the aliphatic moiety can comprise a mixture of aliphatic groups having a range of carbon atoms.
  • the aliphatic moiety can comprise from 10 to 40, from 12 to 38, from 14 to 36, from 16 to 34, from 18 to 32, from 14 to 18, or from 20 to 30 carbon atoms.
  • the aliphatic moiety can contain 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 carbon atoms, where any of the stated values can form an upper or lower endpoint when appropriate.
  • aliphatic moieties examples include, but are not limited to, decyl, dodecyl (lauryl), tetradecyl (myristyl), hexadecyl (palmityl or cetyl), octadecyl (stearyl), eicosyl (arachidyl), and linolenyl groups, including branched derivatives thereof and any mixtures thereof.
  • the aliphatic moiety is bonded to a heteroatom in the heteroaryl moiety.
  • the heteroaryl moiety can be any heteroaryl moiety as described herein.
  • the heteroaryl moiety can be an aryl group having one or more heteroatoms (e.g., nitrogen, oxygen, sulfur, phosphorous, or halonium).
  • heteroaryl moieties that can be used in the aliphatic heteroaryl cations include, but are not limited to, pyrazole, pyridine, pyrazine, pyrimidine, pryidazine, indolizine, isoindole, indole, indazole, imidazole, oxazole, triazole, thiazole, purine, isoquinoline, quinoline, phthalazine, quinooxaline, phenazine, and the like, including substituted derivatives and mixtures thereof.
  • a heteroatom in the heteroaryl moiety is bonded to the aliphatic moiety. When the heteroatom of the heteroaryl is nitrogen, this forms a quaternary ammonium cation, as described herein.
  • aliphatic heteroaryl cations are those having the following structures:
  • R 1 and R 2 are, independently, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxyalkyl group
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 (R 3 -R 9 ) when present, are independently H, a C 1 -C 6 alkyl, a C 1 -C 6 alkoxyalkyl group, a C 1 -C 6 alkoxy group, or an energetic substituents such as nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl cyano, alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and alkoxy azido.
  • both R 1 and R 2 groups are C 1 -C 4 alkyl, with one being methyl, and R 3 -R 9 , when present, are H.
  • Exemplary C 1 -C 6 alkyl groups and C 1 -C 4 alkyl groups include methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, pentyl, iso-pentyl, hexyl, 2-ethylbutyl, 2-methylpentyl, and the like.
  • Corresponding C 1 -C 6 alkoxy groups contain the above C 1 -C 6 alkyl group bonded to an oxygen atom that is also bonded to the cation ring.
  • An alkoxyalkyl group contains an ether group bonded to an alkyl group, and here contains a total of up to six carbon atoms. It is to be noted that there are two isomeric 1,2,3-triazoles. In some examples, all R groups not required for cation formation can be H.
  • all R groups that are not required for cation formation i.e., those other than R 1 and R 2 for compounds other than the imidazolium, pyrazolium, and triazolium cations shown above, are H.
  • a cation that contains a single five-membered ring that is free of fusion to other ring structures is suitable for use herein. Exemplary cations are illustrated below wherein R 1 , R 2 , and R 3 -R 5 , when present, are as defined before.
  • an imidazolium cation that corresponds in structure to Formula A is also suitable, wherein R 1 , R 2 , and R 3 -R 5 , are as defined before.
  • an N,N-1,3-di-(C 1 -C 6 alkyl)-substituted-imidazolium ion can be used; i.e., an imidazolium cation wherein R 3 -R 5 of Formula A are each H, and R 1 and R 2 are independently each a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxyalkyl group.
  • the disclosed ionic liquid compositions can also comprise an aliphatic benzylalkyl ammonium cation.
  • An aliphatic benzylalkyl ammonium cation is a cation that comprises an aliphatic moiety bonded to the nitrogen atom of a benzylalkyl amine moiety.
  • the aliphatic moiety can be as described herein.
  • the benzylalkyl amine moiety can be a benzyl amine where the amine is bonded to an alkyl or cyclic alkyl group, as described herein.
  • One or more types of aliphatic benzylalkyl ammonium cation can be used in the ionic liquid compositions disclosed herein.
  • the aliphatic benzylalkyl ammonium cation suitable for use herein can be prepared by methods known in the art or can be obtained from commercial sources.
  • the aliphatic benzylalkyl ammonium cation can be represented by the following formula:
  • R 10 is an aliphatic group, as described above, R 11 and R 12 are, independent of one another, alkyl groups or cyclic alkyl groups as described herein.
  • one or more of the “R” substituents can be a long chain alkyl group (e.g., the number of carbon atoms is 10 or greater).
  • one or more of the “R” substituents can be a short chain alkyl group (e.g., the number of carbon atoms is less than 10).
  • one of the “R” substituents is a long chain alkyl group and the other two “R” substituents are short chain alkyl groups.
  • the aliphatic benzylalkyl ammonium cation can have any of the aliphatic moieties disclosed herein bonded to any benzylalkyl amine moieties disclosed herein.
  • R 10 in the formula of aliphatic benzylalkyl ammonium cation can be an aliphatic group of from 10 to 40 carbon atoms, e.g., a decyl, dodecyl (lauryl), tetradecyl (myristyl), hexadecyl (palmityl or cetyl), octadecyl (stearyl), or eicosyl (arachidyl) group, and R 11 and R 12 can each be, independent of one another, a methyl, ethyl, propyl, butyl, pentyl, or hexyl group.
  • the aliphatic benzylalkyl ammonium cation can include, but are not limited to, alkyl dimethyl benzyl ammonium cations.
  • alkyl dimethyl benzyl ammonium cations include, but are not limited to, cetyl dimethyl benzyl ammonium, lauryl dimethyl benzyl ammonium, myristyl dimethyl benzyl ammonium, stearyl dimethyl benzyl ammonium, and arachidyl dimethyl benzyl ammonium.
  • the aliphatic benzylalkyl ammonium cation can include, but are not limited to, alkyl methylethyl benzyl ammonium cations.
  • alkyl methylethyl benzyl ammonium cations include, but are not limited to, cetyl methylethyl benzyl ammonium, lauryl methylethyl benzyl ammonium, myristyl methylethyl benzyl ammonium, stearyl methylethyl benzyl ammonium, and arachidyl methylethyl benzyl ammonium.
  • a dialiphatic dialkyl ammonium cation is a compound that comprises two aliphatic moieties and two alkyl moieties bonded to a nitrogen atom.
  • the aliphatic moieties can be the same or different and can be any aliphatic group as described above.
  • the alkyl moieties can be the same or different can be any alkyl group as described above.
  • the two aliphatic moieties can have 10 or more carbon atoms and the two alkyl moieties can have less than 10 carbon atoms.
  • the two aliphatic moieties can have less than 10 carbon atoms and the two alkyl moieties can have 10 or more carbon atoms.
  • One or more types of dialiphatic dialkyl ammonium cations can be used in the ionic liquid compositions disclosed herein.
  • dialiphatic dialkyl ammonium cation can be di-dodecyl dimethyl ammonium, di-tetradecyl dimethyl ammonium, dihexadecyl dimethyl ammonium, and the like, including combinations thereof.
  • the disclosed ionic liquid compositions can also comprise a tetraalkyl ammonium cation.
  • Suitable tetraalkyl ammonium cations comprise four alkyl moieties, as disclosed herein.
  • a tetraalkyl ammonium cation can comprise one long chain alkyl moiety (e.g., 10 or more carbon atoms in length) and three short chain alkyl moieties (e.g., less than 10 carbon atoms in length).
  • tetraalkyl ammonium cations that can be included in the disclosed ionic liquid compositions include, but are not limited to, cetyl trimethyl ammonium, lauryl trimethyl ammonium, myristyl trimethyl ammonium, stearyl trimethyl ammonium, arachidyl trimethyl ammonium, or mixtures thereof.
  • Other examples include, but are not limited to, cetyl dimethylethyl ammonium, lauryl dimethylethyl ammonium, myristyl dimethylethyl ammonium, stearyl dimethylethyl ammonium, arachidyl dimethylethyl ammonium, or mixtures thereof.
  • cations that are suitable for use in the disclosed methods and compositions are compounds that contain metals.
  • any compound that contains a metal atom can be a suitable cation.
  • Organometallic compounds or metal complexes commonly have one or more metal atom in a positive oxidation state.
  • metals that can be present in a suitable cation include, but are not limited to, lithium, sodium, potassium beryllium, magnesium, calcium, strontium, chromium, manganese, iron, cobalt, nickel, copper, and zinc.
  • Silver nanoparticles can also be used.
  • organometallic cations include, but are not limited to, metallocenium, alkylgermanyl, alkyltin, or alkylsilyl (e.g., trimethylsilylium, triethylsilylium, tris(trimethylsilyl)silylium, tribenzylsilylium, triphenylsilylium, tricyclohexylsilylium, and dimethyloctadecylsilylium).
  • metallocenium alkylgermanyl, alkyltin, or alkylsilyl (e.g., trimethylsilylium, triethylsilylium, tris(trimethylsilyl)silylium, tribenzylsilylium, triphenylsilylium, tricyclohexylsilylium, and dimethyloctadecylsilylium).
  • Suitable group of quaternary ammonium cations are those that have been prepared by esterifying a compound containing a carboxylic acid moiety or transesterifying a compound with an ester moiety with a choline moiety.
  • Such choline esters can be biofriendly, permanent ions that are amenable to being added to various compounds while still being easily cleavable under physiological conditions.
  • the choline esters can be used to increase the solubility and bioavailability of many neutral compounds.
  • Futher examples of cations include (2-hydroxyethyl)dimethylundecyloxymethylammonium, (2-acetoxyethyl)heptyloxymethyldimethylammonium, and (2-acetoxyethyl)dodecyloxymethyldimethylammonium, mepenzolate, sulfathiazole, thimerosal, and valproic acid.
  • the cation can be an energetic cation as disclosed in Katritzky et al., “ILs Based on Energetic Imidazolium Cations: Nitro- and Nitrile-substituted N,N′ Dialkylimidazolium Salts” New J Chem 30:349, 2006, which is incorporated by reference herein at least for its teachings of energetic ions.
  • anionic compounds that can be present in the disclosed ionic liquids are compounds that contain oxygen atoms.
  • Oxygen atoms can exist or can be converted to negatively charged, anionic species, for example, through deprotonation of alcohols or acids, through saponification of esters, or through alkylation of ketones.
  • compounds that contain sulfur atoms can also exist or be converted to anionic species through similar reactions.
  • compounds that contain nitrogen atoms, especially nitrogen atoms adjacent to electron withdrawing groups or resonance stabilizing structures can be converted to anions through deprotonation.
  • any compound that contains an oxygen, sulfur, or nitrogen atom can be a suitable anion for the disclosed ionic liquid compositions.
  • Suitable anions include, but are not limited to, halides (e.g., fluoride, chloride, bromide, and iodide), sulfates (SO 4 ⁇ ), carbonates, bicarbonates, phosphates, phosphates, nitrates (NO 3 ⁇ ), nitrites (NO 2 ⁇ ), acetates (CH 3 CO 2 ⁇ ), and the like.
  • halides e.g., fluoride, chloride, bromide, and iodide
  • SO 4 ⁇ sulfates
  • carbonates bicarbonates
  • nitrites NO 2 ⁇
  • acetates CH 3 CO 2 ⁇
  • Other examples of anions include, but are not limited to PF 6 ⁇ that is immiscible in water and BF 4 ⁇ that is miscible in water depending on the ratio of ionic liquid to water,
  • TfO triflate
  • NfO nonaflate
  • CF 3 (CF 2 ) 3 SO 2 ⁇ bis(triflyl)amide
  • Tf 2 N bis(triflyl)amide
  • TA trifluoroacetate
  • HB heptaflurorobutanoate
  • ionic liquids include haloaluminates, such as chloroaluminate.
  • saccharin and acesulfame are suitable anions contemplated herein.
  • Such anions can be used when one desires to prepare an ionic liquid composition that has sweetness as one of its desired properties.
  • saccharin and acesulfame can be combined with pharmaceutically active cations to prepare sweet tasting ionic liquids that have pharmaceutical activity.
  • anions include piperacillin, folic acid, ibuprofen, fast green FCF, docusate, acesulfamate, penicillin G, Colawet MA-80, salicylic acid, saccharinate, sulfacetamide, naproxen, benzoate, diclofenac, and trans-cinnamic acid.
  • Suitable anions include, but are not limited to, substituted and un-substituted imidazolates, 1,2,3-triazolates, and 1,2,4-triazolates, benzimidazolates, benz-1,2,3-triazolates, as shown bellow:
  • R 13 , R 14 , R 15 , R 16 , R 17 , (R 13-17 ), when present, are independently H, a C 1 -C 6 alkyl, a C 1 -C 6 alkoxyalkyl group, a C 1 -C 6 alkoxy group, or energetic substituents like nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl cyano, alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and alkoxy azido.
  • Exemplary C 1 -C 6 alkyl groups and C 1 -C 4 alkyl groups include methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, pentyl, iso-pentyl, hexyl, 2-ethylbutyl, 2-methylpentyl, and the like.
  • Corresponding C 1 -C 6 alkoxy groups contain the above C 1 -C 6 alkyl group bonded to an oxygen atom that is also bonded to the cation ring.
  • An alkoxyalkyl group contains an ether 10 group bonded to an alkyl group, and here contains a total of up to six carbon atoms. It is to be noted that there are two isomeric 1,2,3-triazoles.
  • all R groups not required for anion formation can be H.
  • Examples of compounds that exist as cations in some environments and anions in other environments include, but are not limited to, 1,3-dimethylimidazolium, 1-butyl-3-methylimidazolium, 1,2,3-triazolium, tetrazolium, 1,2,4-triazolium, 1,3-dimethyl-1,2,3-triazolium, and 1,3-dimethyl-4-nitroimidazolium, which exist as a cations, and 4-nitroimidazolate, 4,5-dinitroimidazolate, 3,5-dinitro-1,2,4-triazolate, tetrazolate, 5-aminotetrazolate, 2-nitroimidazolate, which exist as an anion.
  • Those separate ions can still form single product ionic liquids.
  • Examples of compounds that can change from an anion in one environment to a cation in another environment due to chemical modifications are the sulfur ylides through the reaction of a sulfide with methyliodide to form the sulfonium ion.
  • one or more of the ions in the disclosed ionic liquid compositions can be a pharmaceutical active.
  • Pharmaceutical actives that exist as ions or can be converted to ions, and which are suitable for use in preparing the disclosed ionic liquid compositions include the following categories and specific examples. It is not intended that the category be limited by the specific examples. Those of ordinary skill in the art will be able to readily identify those pharmaceutical actives that can be used in the disclosed methods and compositions.
  • a compound with a given property or activity can be identified by consulting various sources, such as the Merck Index (13 th Edition, Wiley, 2001), The United States Pharmacopeia-National Formulary (USP-NF), and the FDA's Orange book, which are each incorporated by reference herein at least for their teachings of pharmaceutical actives.
  • USP-NF United States Pharmacopeia-National Formulary
  • FDA's Orange book which are each incorporated by reference herein at least for their teachings of pharmaceutical actives.
  • the skilled artisan can determine whether the compound is ionic or can be made ionic. Such determinations can be performed based on the compound's structure, which can readily be determined by consulting the sources mentioned herein or experimentally. Knowing a compound's structure can readily reveal if the compound is ionic.
  • a compound is not ionic, but contains an ion forming moiety (e.g., nitrogen, oxygen, sulfur, or metal atoms, as described herein), the compound can be converted to an ion and then combined with a suitable counterion to prepare the disclosed ionic liquid compositions.
  • an ion forming moiety e.g., nitrogen, oxygen, sulfur, or metal atoms, as described herein
  • the compound can be converted to an ion and then combined with a suitable counterion to prepare the disclosed ionic liquid compositions.
  • Some specific examples of pharmaceutical actives that can be used in the disclosed ionic liquids include, but are not limited to, aspirin, LIBRIUMTM, isoniazid, penicillin, PRONTOSILTM, cisplatin, 6-mercaptopurine, RITUXANTM, TAXOLTM, phenobarbital, PROZACTM, ALLEGRATM, VIOXXTM, quinine, ivermectin, L-dopa, THORAZINETM, salvarsan, TAGAMETTM, AZT, crixivan, salbutamol, digoxin, fluride, LOVASTATINTM, erythropoietin, hydrocortisone, insulin, oral contraceptives, oxytocin, PREMARINTM, RU-486, thyroxine, thalidomide, cyclosporine, fentanyl, methadone, morphine, botox, vitamins, FOSAMAXTM, RITALINTM
  • compositions examples include, but are not limited to, pantoprazole, sold under the trade names PROTONLXTM and PANTOZOLTM, and rabeprazole, sold under the trade names ACIPHEXTM and PARIETTM, which are used to treat gastrointestinal disorders.
  • pantoprazole sold under the trade names PROTONLXTM and PANTOZOLTM
  • rabeprazole sold under the trade names ACIPHEXTM and PARIETTM
  • risedronate sold under the trade name ACTONELTM
  • alendronate sold under the trade name FOSAMAXTM
  • suitable compounds that can be used to prepare the disclosed ionic liquid compositions.
  • losartan sold under the trade names NU-LOTANTM, COZAARTM, and HYZAARTM
  • fosinopril sold under the trade name MONOPRILTM
  • Atorvastatin sold under the trade name LIPITORTM
  • pravastatin sold under the trade name PRAVACHOLTM
  • montelukast which is used to treat asthma and is sold under the trade name SINGULAIRTM.
  • the following table illustrates further examples of pharmaceutical actives that are ionic or can be made ionic and combined with other ions to form the disclosed ionic liquid compositions.
  • 3992379 Function Antibacterial (Leprostatic) Acetosulfone Sodium ⁇ 285° U.S. Pat. No. 2358365 Dapsone 175- 176° FR 829926 Avlosulfon, Croysulfone, Diphenasone, Disulone, Dumitone, Eporal, Novophone, Sulfona-Mae, Sulphadione, Udolac Function: Antibacterial (Tuberculostatic) Benzoylpas 260- 261° GB 676363 Cyamelide Function: Anticoagulant Picotamide 124° U.S. Pat. No. 3973026 Function: Anticonvulsant Acetylphen- eturide 100- 101° U.S. Pat.
  • 3455999 Function Antirickettsial Chloram- phenicol 150- 151° U.S. Pat. No. 2839577 Function: Antiseptic/Disinfectant Benzox- onium Chloride 107- 109° CH 306648 Absonal, Bactofen, Bialcol Cetalkonium Chloride 59° U.S. Pat. No. 2075958 Banicol, Acetoquate CDAC, Ammonyx G, Zettyn, Ammonyx T, Cetol Function: Antispasmodic Alibendol 95° U.S. Pat. No. 3668238 Cebera Ambutonium Bromide 228- 229° Function: Antisyphilitic Arsh- penamine U.S. Pat. No.
  • Elecor Function Carbonic Anhydrase Inhibitor Aceta- zolamide 258- 259° U.S. Pat. No. 2554816 Acetamox, Atenezol, Diamox, Didoc, Diuriwas, Donmox, Edemox, Fonurit, Glaupax Flumeth- iazide 305- 307° U.S. Pat. No. 3040042 Ademol, Fludemil Function: Cardioprotective Acadesine 213- 214° Arasine, Protara Cariporide 90-94° U.S. Pat. No. 5591754 Function: Cardotonic Levo- simendan 210- 214° U.S. Pat. No.
  • 2667442 Function Dopamine Receptor Agonist Pergolid 206- 209° U.S. Pat. No. 4166182 Pramipexole Dihydro- chloride 296- 298° U.S. Pat. No. 4886812 Mirapex, Mirapexin, Sifrol Function: Dopamine Receptor Antagonist Amisulpride 126- 127° U.S. Pat. No. 4401822 Sulpiride 178- 180° U.S. Pat. No.
  • Neophryn Function Naroctic Antagonist Cyclazocine 201- 204° BE 611000 Ami- phenazole 163- 164° Dizol, Daptazole, Daptazile, Fenamizol Function: Neuraminidase Inhibitor Zanamivir 256° WO 9116320 Function: Neuromuscular Blocking Agent Succinyl- choline Bromide/ Chloride/ Iodide 156- 163° Fazadinium Bromide 215° U.S. Pat. No.
  • 4479802 Function Respiratory Stimulant Dimefline 213- 214° U.S. Pat. No. 3147258 Fominoben 122- 123° U.S. Pat. No. 3661903 Function: Sclerosing Agent 2-Hexyl- decanoic Acid 140- 150° Sodium Tetradecyl Sulfate Sotradecol, Tergitol Function: Sedative/Hypnotic Flurazepam 77-82° U.S. Pat. Nos.
  • Adrenergic adrenalone, amidephrine mesylate, apraclonidine hydrochloride, brimonidine tartrate, dapiprazole hydrochloride, deterenol hydrochloride, dipivefrin, dopamine hydrochloride, ephedrine sulfate, epinephrine, epinephrine bitartrate, epinephryl borate, esproquin hydrochloride, etafedrine hydrochloride, hydroxyamphetamine hydrobromide, levonordefrin, mephentermine sulfate, metaraminol bitartrate, metizoline hydrochloride, naphazoline hydrochloride, norepinephrine bitartrate, oxidopamine, oxymetazoline hydrochloride, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, phenylpropanolamine polistirex
  • Adrenocortical steroid ciprocinonide, desoxycorticosterone acetate, desoxycorticosterone pivalate, dexamethasone acetate, fludrocortisone acetate, flumoxonide, hydrocortisone hemisuccinate, methylprednisolone hemisuccinate, naflocort, procinonide, timobesone acetate, tipredane.
  • Adrenocortical suppressant aminoglutethimide, trilostane.
  • Aldosterone antagonist canrenoate potassium, canrenone, dicirenone, mexrenoate potassium, prorenoate potassium, spironolactone.
  • Amino acid alanine, aspartic acid, cysteine hydrochloride, cystine, histidine, isoleucine, leucine, lysine, lysine acetate, lysine hydrochloride, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine.
  • Ammonia detoxicant arginine: arginine glutamate, arginine hydrochloride.
  • Anabolic bolandiol dipropionate, bolasterone, boldenone undecylenate, bolenol, bolnantalate, ethylestrenol, methenolone acetate, methenolone enanthate, mibolerone, nandrolone cyclotate, norbolethone, pizotyline, quinbolone, stenbolone acetate, tibolone, zeranol.
  • Analgesic acetaminophen, alfentanil hydrochloride, aminobenzoate potassium, aminobenzoate sodium, anidoxime, anileridine, anileridine hydrochloride, anilopam hydrochloride, anirolac, antipyrine, aspirin, benoxaprofen, benzydamine hydrochloride, bicifadine hydrochloride, brifentanil hydrochloride, bromadoline maleate, bromfenac sodium, buprenorphine hydrochloride, butacetin, butixirate, butorphanol, butorphanol tartrate, carbamazepine, carbaspirin calcium, carbiphene hydrochloride, carfentanil citrate, ciprefadol succinate, ciramadol, ciramadol hydrochloride, clonixeril, clonixin, codeine, codeine phosphate, codeine sulfate, conorphone hydrochlor
  • Androgen fluoxymesterone, mesterolone, methyltestosterone, nandrolone decanoate, nandrolone phenpropionate, nostime acetate, oxandrolone, oxymetholone, silandrone, stanozolol, testosterone, testosterone cypionate, testosterone enanthate, testosterone ketolaurate, testosterone phenylacetate, testosterone propionate, trestolone acetate.
  • Anorectic compounds including dexfenfluramine.
  • Anorexic aminorex, amphecloral, chlorphentermine hydrochloride, clominorex, clortermine hydrochloride, diethylpropion hydrochloride, fenfluramine hydrochloride, fenisorex, fludorex, fluminorex, levamfetamine succinate, mazindol, mefenorex hydrochloride, phenmetrazine hydrochloride, phentermine, sibutramine hydrochloride.
  • Antagonist atipamezole, atosiban, bosentan, cimetidine, cimetidine hydrochloride, clentiazem maleate, detirelix acetate, devazepide, donetidine, etintidine hydrochloride, famotidine, fenmetozole hydrochloride, flumazenil, icatibant acetate, icotidine, isradipine, metiamide, nadide, nalmefene, nalmexone hydrochloride, naloxone hydrochloride, naltrexone, nilvadipine, oxilorphan, oxmetidine hydrochloride, oxmetidine mesylate, quadazocine mesylate, ranitidine, ranitidine bismuth citrate, ranitidine hydrochloride, sufotidine, teludipine hydrochloride, tiapamil hydrochloride, tiot
  • Anterior pituitary activator epimestrol.
  • Anterior pituitary suppressant danazol.
  • Anthelmintic albendazole, anthelmycin, bromoxanide, bunamidine hydrochloride, butonate, cambendazole, carbantel lauryl sulfate, clioxanide, closantel, cyclobendazole, dichlorvos, diethylcarbamazine citrate, dribendazole, dymanthine hydrochloride, etibendazole, fenbendazole, furodazole, hexylresorcinol, mebendazole, morantel tartrate, niclosamide, nitramisole hydrochloride, nitrodan, oxantel pamoate, oxfendazole, oxibendazole, parbendazole, piperamide maleate, piperazine, piperazine citrate, piperazine edetate calcium, proclonol, pyrantel pamoate, pyrantel tartrate, pyrvinium
  • Anti-acne adapalene, erythromycin salnacedin, inocoterone acetate, accutane.
  • Anti-adrenergic acebutolol, alprenolol hydrochloride, atenolol, bretylium tosylate, bunolol hydrochloride, carteolol hydrochloride, celiprolol hydrochloride, cetamolol hydrochloride, cicloprolol hydrochloride, dexpropranolol hydrochloride, diacetolol hydrochloride, dihydroergotamine mesylate, dilevalol hydrochloride, esmolol hydrochloride, exaprolol hydrochloride, fenspiride hydrochloride, flestolol sulfate, labetalol hydrochloride, levobetaxolol hydrochloride, levobunolol hydrochloride, metalol hydrochloride, metoprolol, metoprolol tartrate, nadolol, pamatol
  • Anti-allergic amlexanox, astemizole, azelastine hydrochloride, eclazolast, minocromil, nedocromil, nedocromil calcium, nedocromil sodium, nivimedone sodium, pemirolast potassium, pentigetide, pirquinozol, poisonoak extract, probicromil calcium, proxicromil, repirinast, tetrazolast meglumine, thiazinamium chloride, tiacrilast, tiacrilast sodium, tiprinast meglumine, tixanox.
  • Anti-amebic berythromycin, bialamicol hydrochloride, chloroquine, chloroquine hydrochloride, chloroquine phosphate, clamoxyquin hydrochloride, clioquinol, emetine hydrochloride, iodoquinol, paromomycin sulfate, quinfamide, symetine hydrochloride, teclozan, tetracycline, tetracycline hydrochloride.
  • anti-androgen benorterone, cioteronel, cyproterone acetate, delmadinone acetate, oxendolone, topterone, zanoterone.
  • Anti-anemic epoetin alfa, epoetin beta, ferrous sulfate, dried, leucovorin calcium.
  • Anti-anginal amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, carvedilol, cinepazet maleate, metoprolol succinate, molsidomine, monatepil maleate, primidolol, ranolazine hydrochloride, tosifen, verapamil hydrochloride.
  • Anti-anxiety agent adatanserin hydrochloride, alpidem, binospirone mesylate, bretazenil, glemanserin, ipsapirone hydrochloride, mirisetron maleate, ocinaplon, ondansetron hydrochloride, panadiplon, pancopride, pazinaclone, serazapine hydrochloride, tandospirone citrate, zalospirone hydrochloride.
  • Anti-asthmatic ablukast, ablukast sodium, azelastine hydrochloride, bunaprolast, cinalukast, crornitrile sodium, cromolyn sodium, enofelast, isamoxole, ketotifen fumarate, levcromakalim, lodoxamide ethyl, lodoxamide tromethamine, montelukast sodium, ontazolast, oxarbazole, oxatomide, piriprost, piriprost potassium, pirolate, pobilukast edamine, quazolast, repirinast, ritolukast, sulukast, tetrazolast meglumine, tiaramide hydrochloride, tibenelast sodium, tomelukast, tranilast, verlukast, verofylline, zarirlukast.
  • Anti-atherosclerotic mifobate, timefuronc.
  • Anticholelithic monoctanoin.
  • Anticholelithogenic chenodiol, ursodiol.
  • Anticholinergic alverinc citrate, anisotropine methylbromide, atropine, atropine oxide hydrochloride, atropine sulfate, belladonna, benapryzine hydrochloride, benzetimide hydrochloride, benzilonium bromide, biperiden, biperiden hydrochloride, biperiden lactate, clidinium bromide, cyclopentolate hydrochloride, dexetimide, dicyclomine hydrochloride, dihexyverine hydrochloride, domazoline fumarate, elantrine, elucaine, ethybenztropine, eucatropine hydrochloride, glycopyrrolate, heteronium bromide, homatropine hydrobromide, homatropine methylbromide, hyoscyamine, hyoscyamine hydrobromide, hyoscyamine sulfate, isopropamide io
  • Anticoagulant ancrod, anticoagulant citrate dextrose solution, anticoagulant citrate phosphate dextrose adenine solution, anticoagulant citrate phosphate dextrose solution, anticoagulant heparin solution, anticoagulant sodium citrate solution, ardeparin sodium, bivalirudin, bromindione, dalteparin sodium, desirudin, dicumnarol, heparin calcium, heparin sodium, lyapolate sodium, nafamostat mesylate, phenprocoumon, tinzaparin sodium, warfarin sodium.
  • Anticonvulsant albutoin, ameltolide, atolide, buramate, carbamazepine, cinromide, citenamide, clonazepam, cyheptamide, dezinamide, dimethadione, divalproex sodium, eterobarb, ethosuximide, ethotoin, flurazepam hydrochloride, fluzinamide, fosphenytoin sodium, gabapentin, ilepcimide, lamotrigine, magnesium sulfate, mephenytoin, mephobarbital, methetoin, methsuximide, milacemide hydrochloride, nabazenil, nafimidone hydrochloride, nitrazepam, phenacemide, phenobarbital, phenobarbital sodium, phensuximide, phenytoin, phenytoin sodium, primidone, progabide, ralitoline,
  • Antidepressant adatanserin hydrochloride, adinazolam, adinazolam mesylate, alaproclate, aletamine hydrochloride, amedalin hydrochloride, amitriptyline hydrochloride, amoxapine, aptazapine maleate, azaloxan fuimarate, azepindole, azipramine hydrochloride, bipenamol hydrochloride, bupropion hydrochloride, butacetin, butriptyline hydrochloride, caroxazone, cartazolate, ciclazindol, cidoxepin hydrochloride, cilobamine mesylate, clodazon hydrochloride, clomipramine hydrochloride, cotinine fumarate, cyclindole, cypenamine hydrochloride, cyprolidol hydrochloride, cyproximide, daledalin tosylate, dapo
  • Antidiabetic acetohexamide, buformin, butoxamine hydrochloride, camiglibose, chlorpropamide, ciglitazone, englitazone sodium, etoformin hydrochloride, gliamilide, glibornuride, glicetanile sodium, gliflumide, glipizide, glucagon, glyburide, glyhexamide, glymidine sodium, glyoctamide, glyparamide, insulin, insulin, dalanated, insulin human, insulin human, isophane, insulin human zinc, insulin human zinc, extended, insulin, isophane, insulin lispro, insulin, neutral, insulin zinc, insulin zinc, extended, insulin zinc, prompt, linogliride, linogliride fumarate, metformin, methyl palmoxirate, palmoxirate sodium, pioglitazone hydrochloride, pirogliride tartrate, proinsulin human, seglitide a
  • Antidiarrheal rolgamidine, diphenoxylate hydrochloride (lomotil), metronidazole (flagyl), methylprednisolone (medrol), sulfasalazine (azulfidine).
  • Antidiuretic argipressin tannate, desmopressin acetate, lypressin.
  • Antidote dimercaprol, edrophonium chloride, fomepizole, leucovorin calcium, levoleucovorin calcium, methylene blue, protamine sulfate.
  • Anti-emetic alosetron hydrochloride, batanopride hydrochloride, bemesetron, benzquinamide, chlorpromazine, chlorpromazine hydrochloride, clebopride, cyclizine hydrochloride, dimenhydrinate, diphenidol, diphenidol hydrochloride, diphenidol pamoate, dolasetron mesylate, domperidone, dronabinol, fludorex, flumeridone, galdansetron hydrochloride, granisetron, granisetron hydrochloride, lurosetron mesylate, meclizine hydrochloride, metoclopramide hydrochloride, metopimazine, ondansetron hydrochloride, pancopride, prochlorperazine, prochlorperazine edisylate, prochlorperazine maleate, promethazine hydrochloride, thiethyl
  • Anti-epileptic felbamate, loreclezole, tolgabide.
  • Anti-estrogen clometherone, dehnadinone acetate, nafoxidine hydrochloride, nitromifene citrate, raloxifene hydrochloride, tamoxifen citrate, toremifene citrate, trioxifene mesylate.
  • Antifibrinolytic nafamostat mesylate.
  • Antifungal acrisorcin, ambruticin, amphotericin b, azaconazole, azaserine, basifuingin, bifonazole, biphenamine hydrochloride, bispyrithione magsulfex, butoconazole nitrate, calcium undecylenate, candicidin, carbol-fuichsin, chlordantoin, ciclopirox, ciclopirox olamine, cilofungin, cisconazole, clotrimazole, cuprimyxin, denofungin, dipyrithione, doconazole, econazole, econazole nitrate, enilconazole, ethonam nitrate, fenticonazole nitrate, filipin, fluconazole, flucytosine, fingimycin, griseofulvin, hamycin, isoconazole, itraconazole, kalafungin, ketoconazo
  • Antiglaucoma agent alprenoxime hydrochloride, colforsin, dapiprazole hydrochloride, dipivefrin hydrochloride, naboctate hydrochloride, pilocarpine, pimabine.
  • Antihemophilic antihemophilic factor.
  • Antihemorrhagic poliglusam.
  • Antihistaminic acrivastine, antazoline phosphate, astemizole, azatadine maleate, barmastine, bromodiphenhydramine hydrochloride, brompheniramnine maleate, carbinoxamine maleate, cetirizine hydrochloride, chlorpheniramine maleate, chlorpheniramine polistirex, cinnarizine, clemastine, clemastine fuimarate, closiramine aceturate, cycliramine maleate, cyclizine, cyproheptadine hydrochloride, dexbrompheniramnine maleate, dexchlorpheniramine maleate, dimethindene maleate, diphenhydramine citrate, diphenhydramnine hydrochloride, dorastine hydrochloride, doxylamine succinate, ebastine, levocabastine hydrochloride, loratadine, mianserin hydrochloride, noberastine
  • Antihyperlipidemic cholestyramine resin, clofibrate, colestipol hydrochloride, crilvastatin, dalvastatin, dextrothyroxine sodium, fluvastatin sodium, gemfibrozil, lecimibide, lovastatin, niacin, pravastatin sodium, probucol, simvastatin, tiqueside, xenbucin.
  • Antihyperlipoproteinemic acifran, beloxamide, bezafibrate, boxidine, butoxamine hydrochloride, cetaben sodium, ciprofibrate, gemcadiol, halofenate, lifibrate, meglutol, nafenopin, pimetine hydrochloride, theofibrate, tibric acid, treloxinate.
  • Antihypertensive alfuzosin hydrochloride, alipamide, althiazide, amiquinsin hydrochloride, amlodipine besylate, amlodipine maleate, anaritide acetate, atiprosin maleate, belfosdil, bemitradine, bendacalol mesylate, bendroflumethiazide, benzthiazide, betaxolol hydrochloride, bethanidine sulfate, bevantolol hydrochloride, biclodil hydrochloride, bisoprolol, bisoprolol fumarate, bucindolol hydrochloride, bupicomide, buthiazide: candoxatril, candoxatrilat, captopril, carvedilol, ceronapril, chlorothiazide sodium, cicletanine, cilazapril, clonidine, clon
  • Antihypotensive ciclafrine hydrochloride, midodrine hydrochloride.
  • Anti-infective difloxacin hydrochloride, lauryl isoquinolinium bromide, moxalactam disodium, omidazole, pentisomicin, sarafloxacin hydrochloride, protease inhibitors of hiv and other retroviruses, integrase inhibitors of hiv and other retroviruses, cefaclor (CECLORTM), acyclovir (ZOVIRAXTM), norfloxacin (NOROXINTM), cefoxitin (MEFOXINTM), cefuroxime axetil (CEFTINTM), ciprofloxacin (CIPROTM).
  • Anti-infective, topical alcohol, aminacrine hydrochloride, benzethonium chloride: bithionolate sodium, bromchlorenone, carbamide peroxide, cetalkonium chloride, cetylpyridinium chloride: chlorhexidine hydrochloride, clioquinol,.
  • Anti-inflammatory acetominophen, alclofenac, aldlometasone dipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, dif
  • Antikeratinizing agent doretinel, linarotene, pelretin.
  • Antimalarial acedapsone, amodiaquine hydrochloride, amquinate, arteflene, chloroquine, chloroquine hydrochloride, chloroquine phosphate, cycloguanil pamoate, enpiroline phosphate, halofantrine hydrochloride, hydroxychloroquine sulfate, mefloquine hydrochloride, menoctone, mirincamycin hydrochloride, primaquine phosphate, pyrimethamine, quinine sulfate, tebuquine.
  • Antimicrobial aztreonam, chlorhexidine gluconate, imidurea, lycetamine, nibroxane, pirazmonam sodium, propionic acid, pyrithione sodium, sanguinarium chloride, tigemonam dicholine.
  • Antimigraine dolasetron mesylate, naratriptan hydrochloride, sergolexole maleate, sumatriptan succinate, zatosetron maleate.
  • Antimitotic podofilox.
  • Antimycotic amorolfine.
  • Antinauseant buclizine hydrochloride, cyclizine lactate, naboctate hydrochloride.
  • Antineoplastic acivicin, aclarubicin, acodazole hydrochloride, acrqnine, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, cirolemycin,
  • anti-neoplastic compounds include: 20-epi-1,25 dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfuilvene, adecypenol, adozelesin, aldesleukin, ALL-TK antagonists, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, atrsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonist G, antarelix, anti-dorsalizing morphogenetic protein-1, antiandrogen, prostatic carcinoma, antiestrogen, antineoplaston, antisense oligonucleotides, aphidicolin glycinate, apoptosis gene modulators, apoptosis regulators, apurinic acid, ara-CDP-DL-PTBA, arg
  • Anti-cancer supplementary potentiating agents tricyclic anti-depressant drugs (e.g., imipramine, desipramine, amitryptyline, clomiprainine, trimipramine, doxepin, nortriptyline, protriptyline, amoxapine and maprotiline), non-tricyclic anti-depressant drugs (e.g., sertraline, trazodone and citalopram), Ca ++ antagonists (e.g., verapamil, nifedipine, nitrendipine and caroverine), calmodulin inhibitors (e.g., prenylamine, trifluoroperazine and clomipramine), amphotericin B, triparanol analogues (e.g., tamoxifen), antiarrhythmic drugs (e.g., quinidine), antihypertensive drugs (e.g., reserpine), thiol depleters
  • Antineutropenic filgrastim, lenograstim, molgramostim, regramostim, sargramostim.
  • Antiobsessional agent fluvoxamine maleate.
  • Antiparasitic abamectin, clorsulon, ivermectin.
  • benztropine mesylate biperiden, biperiden hydrochloride, biperiden lactate, carmantadine, ciladopa hydrochloride, dopamantine, ethopropazine hydrochloride, lazabemide, levodopa, lometraline hydrochloride, mofegiline hydrochloride, naxagolide hydrochloride, pareptide sulfate, procyclidine hydrochloride, quinetorane hydrochloride, ropinirole hydrochloride, selegiline hydrochloride, tolcapone, trihexyphenidyl hydrochloride.
  • antiperistaltic difenoximide hydrochloride, difenoxin, diphenoxylate hydrochloride, fluperamide, lidamidine hydrochloride, loperamide hydrochloride, malethamer, nufenoxole, paregoric.
  • Antipneumocystic atovaquone.
  • Antiproliferative agent piritrexim isethionate.
  • Antiprostatic hypertrophy sitogluside.
  • Antiprotozoal amodiaquine, azanidazole, bamnidazole, carnidazole, chlortetracycline bisulfate, chlortetracycline hydrochloride, flubendazole, flunidazole, halofuginone hydrobromide, imidocarb hydrochloride, ipronidazole, metronidazole, misonidazole, moxnidazole, nitarsone, partricin, puromycin, puromycin hydrochloride, ronidazole, sulnidazole, tinidazole.
  • Antipruritic cyproheptadine hydrochloride, methdilazine, methdilazine hydrochloride, trimeprazine tartrate.
  • Antipsoriatic acitretin, anthralin, azaribine, calcipotriene, cycloheximide, enazadrem phosphate, etretinate, liarozole fumarate, lonapalene, tepoxalin.
  • Antipsychotic acetophenazine maleate, alentemol hydrobromide, alpertine, azaperone, batelapine maleate, benperidol, benzindopyrine hydrochloride, brofbxine, bromperidol, bromperidol decanoate, butaclamol hydrochloride, butaperazine, butaperazine maleate, carphenazine maleate, carvotroline hydrochloride, chlorpromazine, chlorpromazine hydrochloride, chlorprothixene, cinperene, cintriamide, clomacran phosphate, clopenthixol, clopimozide, clopipazan mesylate, cloroperone hydrochloride, clothiapine, clothixamide maleate, clozapine, cyclophenazine hydrochloride, droperidol, etazolate hydrochloride, fenimide, flu
  • Antirheumatic auranofin, aurothioglucose, bindarit, lobenzarit sodium, phenylbutazone, pirazolac, prinomide tromethamine, seprilose.
  • Antischistosomal becanthone hydrochloride, hycanthone, lucanthone hydrochloride, niridazole, oxamniquine, pararosaniline pamoate, teroxalene hydrochloride.
  • Antiseborrheic chloroxine, piroctone, piroctone olamine, resorcinol monoacetate.
  • antisecretory arbaprostil, deprostil, fenoctimine sulfate, octreotide, octreotide acetate, omeprazole sodium, rioprostil, trimoprostil.
  • Antispasmodic stilonium iodide, tizanidine hydrochloride.
  • Antithrombotic anagrelide hydrochloride, bivalirudin, dalteparin sodium, danaparoid sodium, dazoxiben hydrochloride, efegatran sulfate, enoxaparin sodium, ifetroban, ifetroban sodium, tinzaparin sodium, trifenagrel.
  • Antitussive benzonatate, butamirate citrate, chlophedianol hydrochloride, codeine polistirex, codoxime, dextromethorphan, dextromethorphan hydrobromide, dextromethorphan polistirex, ethyl dibunate, guaiapate, hydrocodone bitartrate, hydrocodone polistirex, levopropoxyphene napsylate, noscapine, pemerid nitrate, pipazethate, suxemerid sulfate.
  • Anti-ulcerative aceglutamide aluminum, cadexomer iodine, cetraxate hydrochloride, enisoprost, isotiquimide, lansoprazole, lavoltidine succinate, misoprostol, nizatidine, nolinium bromide, pantoprazole, pifarnine, pirenzepine hydrochloride, rabeprazole sodium, remiprostol, roxatidine acetate hydrochloride, sucralfate, sucrosofate potassium, tolimidone.
  • Anti-urolithic cysteamine, cysteamine hydrochloride, tricitrates.
  • Benign prostatic hyperplasia therapy agent tamsulosin hydrochloride.
  • Blood glucose regulators human insulin, glucagon, tolazamide, tolbutamide, chloropropamide, acetohexamide and glipizide.
  • Bone resorption inhibitor alendronate sodium, etidronate disodium, pamidronate disodium.
  • Bronchodilator albuterol, albuterol sulfate, azanator maleate, bamifylline hydrochloride, bitolterol mesylate, butaprost, carbuterol hydrochloride, clorprenaline hydrochloride, colterol mesylate, doxaprost, doxofylline, dyphylline, enprofylline, ephedrine, ephedrine hydrochloride, fenoterol, fenprinast hydrochloride, guaithylline, hexoprenaline sulfate, hoquizil hydrochloride, ipratropium bromide, isoetharine, isoetharine hydrochloride, isoetharine mesylate, isoproterenol hydrochloride, isoproterenol sulfate, metaproterenol polistirex, meta
  • Carbonic anhydrase inhibitor acetazolamide, acetazolamide sodium, dichlorphenamide, dorzolamide hydrochloride, methazolamide, sezolamide hydrochloride.
  • Cardiac depressant acecainide hydrochloride, acetylcholine chloride, actisomide, adenosine, amiodarone, aprindine, aprindine hydrochloride, artilide fumarate, azimilide Dihydrochloride, bidisomide, bucainide maleate, bucromarone, butoprozine hydrochloride, capobenate sodium, capobenic acid, cifenline, cifenline succinate, clofilium phosphate, disobutamide, disopyramide, disopyramide phosphate, dofetilide, drobuline, edifolone acetate, emilium tosylate, encainide hydrochloride, flecainide acetate, ibutilide fuimarate, indecainide hydrochloride, ipazilide fumarate, lorajmine hydrochloride, lorcainide hydrochloride
  • Cardioprotectant dexrazoxane, draflazine.
  • Cardiotonic actodigin, amrinone, bemoradan, butopamine, carbazeran, carsatrin succinate, deslanoside, digitalis, digitoxin, digoxin, dobutamine, dobutamine hydrochloride, dobutamine lactobionate, dobutamine tartrate, enoximone, imazodan hydrochloride, indolidan, isomazole hydrochloride, levdobutamine lactobionate, lixazinone sulfate, medorinone, milrinone, pelrinone hydrochloride, pimobendan, piroximone, prinoxodan, proscillaridin, quazinone, tazolol hydrochloride, vesnarinone.
  • Cardiovascular agent dopexamine, dopexamine hydrochloride.
  • Choleretic dehydrocholic acid, fencibutirol, hymecromone, piprozolin, sincalide, tocamphyl.
  • Cholinergic aceclidine, bethanechol chloride, carbachol, demecarium bromide, dexpanthenol, echothiophate iodide, isoflurophate, methacholine chloride, neostigmine bromide, neostigmine methylsulfate, physostigmine, physostigmine salicylate, physostigmine sulfate, pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate, pyridostigmine bromide.
  • Cholinergic agonist xanomeline, xanomeline tartrate.
  • Cholinesterase deactivator obidoxime chloride, pralidoxime chloride, pralidoxime iodide, pralidoxime mesylate.
  • Coccidiostat arprinocid, narasin, semduramicin, semduramicin sodium.
  • Dognition adjuvant ergoloid mesylates, piracetam, pramiracetam hydrochloride, pramiracetam sulfate, tacrine hydrochloride.
  • Cognition enhancer besipirdine hydrochloride, linopirdine, sibopirdine.
  • Diagnostic aid aminohippurate sodium, anazolene sodium, arclofenin, arginine, bentiromide, benzylpenicilloyl polylysine, butedronate tetrasodium, butilfenin, coccidioidin, corticorelin ovine triflutate, corticotropin, repository, corticotropin zinc hydroxide, diatrizoate meglumine, diatrizoate sodium, diatrizoic acid, diphtheria toxin for schick test, disofenin, edrophonium chloride, ethiodized oil, etifenin, exametazime, ferristenc, ferumoxides, ferumoxsil, fluorescein, fluorescein sodium, gadobenate dimeglumine, gadoteridol, gadodiamide, gadopentetate dimegiumine, gadoversetamide, histoplasmin, impromidine hydrochlor
  • Diuretic ambuphylline, ambuside, amiloride hydrochloride, azolimine, azosemide, brocrinat, bumetanide, chlorothiazide, chlorthalidone, clazolimine, clorexolone, ethacrynate sodium, ethacrynic acid, etozolin, fenquizone, furosemide, hydrochlorothiazide, isosorbide, mannitol, mefruside, ozolinone, piretanide, spiroxasone, torsemide, triamterene, triflocin, urea.
  • Dopaminergic agent ibopamine.
  • Ectoparasiticide nifluridide, permethrin.
  • Emetic apomorphine hydrochloride.
  • Enzyme inhibitor acetohydroxamic acid, alrestatin sodium, aprotinin, benazepril hydrochloride, benazeprilat, benurestat, bromocriptine, bromocriptine mesylate, cilastatin sodium, flurofamide, lergotrile, lergotrile mesylate, levcycloserine, libenzapril, pentopril, pepstatin, perindopril, polignate sodium, sodium amylosulfate, sorbinil, spirapril hydrochloride, spiraprilat, taleranol, teprotide, tolfamide, zofenopril calcium.
  • Estrogen chlorotrianisene, dienestrol, diethylstilbestrol, diethylstilbestrol diphosphate, equilin, estradiol, estradiol cypionate, estradiol enanthate, estradiol undecylate, estradiol valerate, estrazinol hydrobromide, estriol, estrofurate, estrogens, conjugated, estrogens, esterified, estrone, estropipate, ethinyl estradiol, fenestrel, mestranol, nylestriol, quinestrol.
  • Fibrinolytic anistreplase, bisobrin lactate, brinolase.
  • Free oxygen radical scavenger pegorgotein.
  • Gastrointestinal motility agents cisapride (PROPULSIDTM), metoclopramide (REGLANTM), hyoscyamine (LEVSINTM).
  • Glucocorticoid amcinonide, beclomethasone dipropionate, betamethasone, betamethasone acetate, betamethasone benzoate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, carbenoxolone sodium, clocortolone acetate, clocortolone pivalate, cloprednol, corticotropin, corticotropin, repository, corticotropin zinc hydroxide, cortisone acetate, cortivazol, descinolone acetonide, dexamethasone, dexamethasone sodium phosphate, diflucortolone, diflucortolone pivalate, flucloronide, flumethasone, flumethasone pivalate, flunisolide, fluocinolone acetonide, fluocinonide, fluocortolone, fluocortolone caproate, fluorometholone, fluperolone
  • Gonad-stimulating principle buserelin acetate, clomiphene citrate, ganirelix acetate, gonadorelin acetate, gonadorelin hydrochloride, gonadotropin, chorionic, menotropins.
  • Hair growth stimulant minoxidil.
  • Hemostatic aminocaproic acid, oxamarin hydrochloride, sulmarin, thrombin, tranexarnic acid.
  • Histamine H2 receptor antagonists ranitidine (ZANTACTM), famotidine (PEPCIDTM), cimetidine (TAGAMETM), nizatidine (AXIDTM).
  • Hormone diethylstilbestrol, progesterone, 17 hydroxy progesterone, medroxyprogesterone, norgestrel, norethynodrel, estradiol, megestrol (megace), norethindrone, levonorgestrel, ethyndiol, ethinyl estradiol, mestranol, estrone, equilin, 17 alpha dihydroequilin, equilenin, 17 alpha dihydroequilenin, 17 alpha estradiol, 17 beta estradiol, leuprolide (LUPRONTM), glucagon, testolactone, clomiphene, human menopausal gonadotropins, human chorionic gonadotropin, urofollitropin, bromocriptine, gonadorelin, luteinizing hormone releasing hormone and analogs, gonadotropins, danazol, testosterone, dehydroepiandros
  • hypolipidemic azalanstat dihydrochloride, colestolone, surfomer, xenalipin.
  • Hmgcoa reductase inhibitors lovastatin (MEVACORTM), simvastatin (ZOCORTM), pravastatin (PRAVACHOLTM), fluvasatin (LESCOLTM).
  • Immunizing agent antirabies serum, antivenin ( latrodectus mactans ), antivenin ( micrurus fulvius ), antivenin ( crotalidae ) polyvalent, BCG vaccine, botulism antitoxin, cholera vaccine, diphtheria antitoxin, diphtheria toxoid, diphtheria toxoid adsorbed, globulin, immune, hepatitis b immune globulin, hepatitis B virus vaccine inactivated, influenza virus vaccine, measles virus vaccine live, meningococcal polysaccharide vaccine group A, meningococcal polysaccharide vaccine group C, mumps virus vaccine live, pertussis immune globulin, pertussis vaccine, pertussis vaccine adsorbed, plague vaccine, poliovirus vaccine inactivated, poliovirus vaccine live oral, rabies immune globulin, rabies vaccine, Rh o (D) immune globulin,
  • Immunomodulator dimepranol acedoben, imiquimod, interferon beta-lb, lisofylline, mycophenolate mofetil, prczatide copper acetate.
  • Immunoregulator azarole, fanetizole mesylate, frentizole, oxamisole hydrochloride, ristianol phosphate, thymopentin, tilomisole.
  • Immunostimulant loxoribine, teceleukin.
  • Immunosuppressant azathioprine, azathioprine sodium, cyclosporine, daltroban, gusperimus trihydrochloride, sirolimus, tacrolimus.
  • Impotence therapy adjunct delequamine hydrochloride.
  • Inhibitor acarbose, atorvastatin calcium, benserazide, brocresine, carbidopa, clavulanate potassium, dazmegrel, docebenone, epoprostenol, epoprostenol sodium, epristeride, finasteride, flurbiprofen sodium, furegrelate sodium, lufironil, miglitol, orlistat, pimagedine hydrochloride, pirmagrel, ponalrestat, ridogrel, sulbactam benzathine, sulbactampivoxil, sulbactam sodium, suronacrine maleate, tazobactam, tazobactam sodium, ticlopidine hydrochloride, tirilazad mesylate, tolrestat, velnacrine maleate, zifrosilone, zileuton.
  • Keratolytic alcloxa, aldioxa, benzoyl peroxide, dibenzothiophene, etarotene, isotretinoin, motretinide, picotrin diolanine, resorcinol, resorcinol monoacetate, salicylic acid, sumarotene, tazarotene, tetroquinone, tretinoin.
  • LHRL agonist deslorelin, goserelin, histrelin, lutrelin acetate, nafarelin acetate.
  • Liver disorder treatment malotilate.
  • Memory adjuvant dimoxamine hydrochloride, ribaminol.
  • Mood regulator fengabine.
  • Mucolytic acetylcysteine, carbocysteine, domiodol.
  • Mucosal protective agents misoprostol (CYTOTECTM).
  • Nasal decongestant nemazoline hydrochloride, pseudoephedrine polistirex.
  • Neuroleptic duoperone fumarate, risperidone.
  • Neuromuscular blocking agent atracurium besylate, cisatracurium besylate, doxacurium chloride, gallamine triethiodide, metocurine iodide, mivacurium chloride, pancuronium bromide, pipecuronium bromide, rocuronium bromide, succinylcholine chloride, tubocurarine chloride, vecuronium bromide.
  • Neuroprotective dizocilpine maleate.
  • NMDA antagonist selfotel.
  • Non-hormonal sterol derivative pregnenolone succinate.
  • Oxytocic carboprost, carboprost methyl, carboprost tromethamine, dinoprost, dinoprost tromethamine, dinoprostone, ergonovine maleate, meteneprost, methylergonovine maleate, oxytocin, sparteine sulfate.
  • Plasminogen activator alteplase, urokinase.
  • Platelet activating factor antagonist lexipafant.
  • Platelet aggregation inhibitor acadesine, beraprost, beraprost sodium, ciprostene calcium, itazigrel, lifarizine, oxagrelate.
  • Potentiator pentostatin, talopram hydrochloride.
  • Progestin algestone acetophenide, amadinone acetate, anagestone acetate, chlormadinone acetate, cingestol, clogestone acetate, clomegestone acetate, desogestrel, dimethisterone, dydrogesterone, ethynerone, ethynodiol diacetate, etonogestrel, flurogestone acetate, gestaclone, gestodene, gestonorone caproate, gestrinone, haloprogesterone, hydroxyprogesterone caproate, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, methynodiol diacetate, norethindrone, norethindrone acetate, norethynodrel, norgestimate, norgestomet, norgestrel, oxo
  • Prostaglandin cloprostenol sodium, fluprostenol sodium, gemeprost, prostalene, sulprostone.
  • Prostate growth inhibitor pentomone.
  • Prothyrotropin protirelin.
  • Pulmonary surface beractant, colfosceril palmitate.
  • Radioactive agent fibrinogen I 125 , fludeoxyglucose F 18 , fluorodopa F 18 , insulin I 125 , insulin I 131 , iobenguane I 123 , iodipamide sodium I 131 , iodoantipyrine I 131 , iodocholesterol I 131 , iodohippurate sodium I 123 , iodohippurate sodium I 125 , iodohippurate sodium I 131 , iodopyracet I 125 , iodopyracet I 131 , iofetamine hydrochloride I 123 , iomethin I 125 , iomethin I 131 , iothalamate sodium I 125 , iothalamate sodium I 131 , iotyrosine I 131 , liothyronine I 125 , liothyronine
  • Regulator calcifediol, calcitonin, calcitriol, clodronic acid, dihydrotachysterol, etidronic acid, oxidronic acid, piridronate sodium, risedronate sodium, secalciferol.
  • Relaxant adiphenine hydrochloride, alcuronium chloride, aminophylline, azumolene sodium, baclofen, benzoctamine hydrochloride, carisoprodol, chlorphenesin carbamate, chlorzoxazone, cinflumide, cinnamedrine, clodanolene, cyclobenzaprine hydrochloride, dantrolene, dantrolene sodium, fenalamide, fenyripol hydrochloride, fetoxylate hydrochloride, flavoxate hydrochloride, fletazepam, flumetramide,-flurazepam hydrochloride, hexafluorenium bromide, isomylamine hydrochloride, lorbamate, mebeverine hydrochloride, mesuprine hydrochloride, metaxalone, methocarbamol, methixene hydrochloride, nafomine malate, is
  • Repartitioning agent cimaterol.
  • Scabicide amitraz, crotamiton.
  • Sclerosing agent ethanolamine oleate, morrhuate sodium, tribenoside.
  • Sedative-hypnotic allobarbital, alonimid, alprazolam, amobarbital sodium, bentazepam, brotizolam, butabarbital, butabarbital sodium, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide hydrochloride, cloperidone hydrochloride, clorethate, cyprazepam, dexclamol hydrochloride, diazepam, dichloralphenazone, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, fosazepam, glutethimide, halazepam, lormetazepam, mecloqualone, meprobamate, methaqualone, midaflur, paraldehyde, pentobarbital, pentobarbital sodium, perlapine, prazepam
  • Selective adenosine al antagonist apaxifylline.
  • Serotonin antagonist altanserin tartrate, amesergide, ketanserin, ritanserin.
  • Serotonin inhibitor cinanserin hydrochloride, fenclonine, fonazine mesylate, xylamidine tosylate.
  • Serotonin receptor antagonist tropanserin hydrochloride.
  • Steroid dexamethasone aceflrate, mometasone furoate.
  • Stimulant amfonelic acid, amphetamine sulfate, ampyzine sulfate, arbutamine hydrochloride, azabon, caffeine, ceruletide, ceruletide diethylamine, cisapride, dazopride fuimarate, dextroamphetamine, dextroamphetamine sulfate, difluanine hydrochloride, dimefline hydrochloride, doxapram hydrochloride, etryptamine acetate, ethamivan, fenethylline hydrochloride, flubanilate hydrochloride, flurothyl, histamine phosphate, indriline hydrochloride, mefexamide, methanphetamine hydrochlo ride, methylphenidate hydrochloride, pemoline, pyrovalerone hydrochloride, xamoterol, xamoterol fumarate.
  • Suppressant amffiutizole, coxchicine, tazofelone.
  • Symptomatic multiple sclerosis fampridine.
  • Thyroid hormone levothyroxine sodium, liothyronine sodium, liotrix.
  • Thyroid inhibitor methimazole, propyithiouracil.
  • Thyromimetic thyromedan hydrochloride.
  • Tranquilizer bromazepam, buspirone hydrochloride, chlordiazepoxide, clazolam, clobazam, clorazepate dipotassium, clorazepate monopotassium, demoxepam, dexmedetomidine, enciprazine hydrochloride, gepirone hydrochloride, hydroxyphenamate, hydroxyzine
  • Hydrochloride hydroxyzine pamoate, ketazolam, lorazepam, lorzafone, loxapine, loxapine succinate, medazepam hydrochloride, nabilone, nisobamate, oxazepam, pentabamate, pirenperone, ripazepam, rolipram, sulazepam, taciamine hydrochloride, temazepam, triflubazam, tybamate, valnoctamide.
  • Amyotrophic lateral sclerosis agents riluzole.
  • Cerebral ischemia agents dextrorphan hydrochloride.
  • Paget's disease agents tiludronate disodium.
  • Unstable angina agents tirofiban hydrochloride.
  • Uricosuric benzbromarone, irtemazole, probenecid, sulfinpyrazone.
  • Vasoconstrictor angiotensin amide, felypressin, methysergide, methysergide maleate.
  • Vasodilator alprostadil, azaclorzine hydrochloride, bamethan sulfate, bepridil hydrochloride, buterizine, cetiedil citrate, chromonar hydrochloride, clonitrate, diltiazem hydrochloride, dipyridamole, droprenilamine, erythrityl tetranitrate, felodipine, flunarizine hydrochloride, fostedil, hexobendine, inositol niacinate, iproxamine hydrochloride, isosorbide dinitrate, isosorbide mononitrate, isoxsuprine hydrochloride, lidoflazine, mefenidil, mefenidil fumarate, mibefradil dihydrochloride, mioflazine hydrochloride, mixidine, nafronyl oxalate, nicardipine hydrochloride, nice
  • Wound healing agent ersofermin.
  • Xanthine oxidase inhibitor allopurinol, oxypurinol.
  • Other pharmaceutical agents include: 1-decpyrrolidinone, 1-dodecpyrrolidinone, 16 ⁇ -fluoroestradiol, 16-epiestriol, 16 ⁇ -gitoxin, 17 ⁇ estradiol, 17 ⁇ estradiol, 1 alpha-hydroxyvitamin D2,2′-nor-cGMP, 20-epi-1,25 dihydroxyvitamin D3, 22-oxacalcitriol, 2CVV, 3-isobutyl GABA, 6-FUDCA, 7-methoxytacrine, abamectin, abanoquil, abecarnil, abiraterone, acadesine, acamprosate, acarbose, aceclofenac, acemannan, acetomepregenol, acetyl-L-carnitine, acetylcysteine, N-acetylmethadol, acifran, acipimox, acitemate, acitre
  • one or more of the ions in the disclosed ionic liquids can be an antibacterial. That is the one or more kinds of cations, one or more kinds of anions, or both cations and anions can be an antibacterial. Many of suitable antibacterial have already been disclosed herein (e.g., many QACs have antibacterial properties).
  • Suitable antibacterial agents include, but are not limited to, acedapsone, acetosulfone sodium, alamecin, alexidine, amdinocillin, amdinocillin pivoxil, amicycline, amifloxacin, amifloxacin mesylate, amikacin, amikacin sulfate, aminosalicyhc acid, aminosalicylate sodium, amoxicillin, amphomycin, ampicillin, ampicillin sodium, apalcillin sodium, apramycin, aspartocin, astromicin sulfate, avilamycin, avoparcin, azithromycin, azlocillin, azlocillin sodium, bacampicillin hydrochloride, bacitracin, bacitracin methylene disalicylate, bacitracin zinc, bambermycins, benzoylpas calcium, berythromycin, betamicin sulfate, biapenem, bini
  • Penicillin G which is used as an antibacterial agent for infections including pneumonia, meningitis, and skin, bone, joint, stomach, blood, and heart valve infections, is a particular example suitable for use herein.
  • tazobactum sold under the trade names ZOSYNTM and TAZOCINTM
  • ceftrioxone sold under the trade name ROCEPHINTM
  • metronidazol sold under the trade name FLAGYLTM
  • FLAGYLTM are also used to treat bacterial infections and are further examples of suitable compounds that can be used to prepare the disclosed ionic liquids.
  • antibacterials can be identified based on the desired properties of the antibacterial and whether the antibacterial active is or can be converted into an ion. As noted, identification of whether an antibacterial active is an ion or can be converted into an ion can be done by a skilled artisan inspecting the chemical structure of the antibacterial.
  • one or more of the ions in the disclosed ionic liquids can be an antiviral.
  • suitable antiviral actives include, but are not limited to, acemannan, acyclovir, acyclovir sodium, adefovir, alovudine, alvircept sudotox, amantadine hydrochloride, aranotin, arildone, atevirdine mesylate, avridine, cidofovir, cipamfylline, cytarabine hydrochloride, delavirdine mesylate, desciclovir, didanosine, disoxaril, edoxudine, enviradene, enviroxime, famciclovir, famotine hydrochloride, fiacitabine, fialuridine, fosarilate, foscamet sodium, fosfonet sodium, ganciclo
  • antivirals can be identified based on the desired properties of the antiviral and whether the antiviral is or can be converted into an ion. As noted, identification of whether an antiviral is an ion or can be converted into an ion can be done by a skilled artisan inspecting the chemical structure of the antiviral.
  • one or more of the ions in the disclosed ionic liquids can be a pesticide. Included within the meaning of “pesticide” are insecticides and fingicides.
  • suitable pesticides include, but are not limted to, carfentrazone-ethyl, sulfentrazone, clomazone, diclofop-methyl, oxamyl propargite, prosulfuron, pyridate, pyriftalid, S-metolachlor, simazine, terbuthylazine, terbutryn, triasulfuron, trifloxysulfuron, trinexapac-ethyl, ametryn, atrazine, benoxacor, bifenthrin, butafenacil, choline azide, chlortoluron, cinosulfuron, clodinafop, cloquintocet, DEET, desmetryn, dicamba, dimethachlor, dimethametryn, DTPA NaFe, EDDHA NaFe, fenclorim, flumetralin, fluometuron, fluthiacetmethyl, halos
  • Prohexadione is a FDA approved reduced risk fungicide and is also useful for the disclosed ionic liquids. Further examples of suitable pesticides can be found in The Pesticide Manual, 11 th Edition, British Crop Protection Council, 1997, which is incorporated by reference herein at least for its teaching of pesticides.
  • Suitable pesticides can be identified based on the desired properties of the pesticide and whether the pesticide is or can be converted into an ion. As noted, identification of whether a pesticide is an ion or can be converted into an ion can be done by a skilled artisan inspecting the chemical structure of the pesticide.
  • one or more of the ions in the disclosed ionic liquids can be a herbicide.
  • suitable herbicides include, but are not limited to, carfentrazone, imazapyr, benefin, acifluorfen, and 2-[2-chloro-3-(2,2,2-trifluoroethoxymethyl)-4-methylsulfonylbenzoyl]cyclohexane-1.
  • herbicides include inhibitors of the biosynthesis of branched amino acids such as ethoxysulfuron, flumetsulam, halosulfuron, imazamox, imazapyr, imazaquin, imazethapyr, metosulam, nicosulfuron, primisulfuron, prosulfuron, rimsulfuron, thifensulfuron-methyl, triflusulfuron, N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-dimethylaminocarbonyl-5-formylaminobenzenesulfonamide (Foramsulfuron), and the like.
  • branched amino acids such as ethoxysulfuron, flumetsulam, halosulfuron, imazamox, imazapyr, imazaquin, imazethapyr, metosulam, nicosulfuron, primisulfuron, prosulfuron, rim
  • suitable herbicides include inhibitors of the photosynthesis electron transport such as ametryne, atrazine, bromoxynil, cyanazine, diuron, hexazinone, metribuzin, pyridate, terbuthylazine, and the like.
  • suitable herbicides for the disclosed ionic liquids include synthetic auxins such as copyralid, dicamba, diflufenzopyr, fluroxypyr, and the like.
  • Inhibitors of fatty acid biosynthesis such as butylate, EPTC, fenoxaprop-P-ethyl, and the like, can also be used in the disclosed ionic liquid compositions.
  • suitable herbicides can include inhibitors of cell division such as acetochlor, alachlor, dimethenamid, flufenacet, mefenacet, metolachlor, S-metolachlor, thenylchlor, and the like.
  • the herbicide can be an inhibitor of protoporphyrinogen oxidase, such as fluthiacet-methyl, carfentrazone-ethyl, and the like.
  • Inhibitors of hydroxyphenylpyruvate dioxygenase such as isoxaflutole, mesotrione, sulcotrione, 4-(4-trifluoromethyl-2-methylsulfonylbenzoyl)-5-hydroxy-1-methyl-3-methylpyrazole, and the like, can also be used.
  • suitable herbicides include, but are not limited to, glyphosate, pendimethalin, trifluralin, asulam, triaziflam, diflufenican, glufosinate-ammonium, and the like. Clofencet, fluroxpyr, mesosulfuron, diflufenzopyr are further examples of suitable herbicides and they are FDA approved.
  • ком ⁇ онентs that are ions or can be converted to ions can be used in the disclosed ionic liquid compositions.
  • Specific examples of these include, but are not limited to, the food additives Allura Red AC (FD&C Red No.40), Tartrazine (FD&C Yellow No. 5), Indigotine (FD&C Blue No.2), Erythrosine (FD&C Red No.3), and Sunset Yellow (FD&C Yellow No. 6), which are FDA-approved color additives for food use.
  • nutraceuticals such as fatty acids, cholesterols, vitamins, minerals, and trace elements can be suitable ions for the disclosed ionic liquid compositions.
  • SEA-NIN-211 is an antifoulant that can be used as an ion id the disclosed compositions.
  • the disclosed ionic liquid compositions can also include high energy ingredients as well as explosive materials.
  • the ability to prepare a particular composition with high energy content substituents (fuel) on one ion and high oxygen balance (oxidizers) on the other ion opens wide applicability in today's high energy compounds industry.
  • the ability to independently form differentially functionalized groups of ions, then chose two of interest and combining them on demand to form desired strength energetic material (Scheme 1) opens the doors for the quick preparation of customizable energetic materials (e.g., explosives with pre-designed power) and more safe storage technique of those energetic materials since the components are separated before usage.
  • the disclosed compositions can be prepared according to one of the following reaction protocols.
  • En is an energetic functional group containing either high oxygen or nitrogen content (including but not limited to: nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl cyano, alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and alkoxy azido),
  • IA ⁇ is an innocuous anion
  • IC+ is an innocuous cation
  • [IC][IA] is an easily removable and harmless byproduct from the metathesis reaction.
  • solvent system media solvent system is the solvent or the mixture of the solvents in which at least one of the starting materials dissolves).
  • ionic liquid compositions include, but are not limited to, the mixture of at least two components of functionalized 5- and 6-membered, and bicyclic fused ring heterocyclic cations and anions containing 1, 2, 3, 4, or 5 atoms of nitrogen in the ring structure, where all carbon and nitrogen atoms in the ring structure can be functionalized with additional substituents such as alkyl, allyl, aryl, nitro, nitrile, azido, hydroxyl, carboxylic acid, ester, amide, amine, aldehyde, ketone, epoxy, or functionalized alkyl and aryl groups (with any functional mentioned above). Examples of such components (cations and/or anions) are shown below.
  • R 1 , R 2 , R 3 , R 4, R 5 , R 6 , and R 7 are, independent of one another, not present, H, alkyl, alkenyl, alkynyl, allyl, aryl, nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl cyano, alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and alkoxy azido, nitrile, isonitrile, carboxylic acid, ester, ether, CO 2 NR 8 2 , CO 2 NHR 8 , CO 2 NH 2 , amine, NHR 8 , NR 8 2 , ketone, aldehyde, or epoxy, wherein R 8 is H, alkyl alkenyl, alkynyl, allyl, aryl, carboxylic acid, ester, ether, ketone, or aldehyde.
  • model compounds (4) which may undergo further modification in terms of introduced functions (on the cation precursor (1), anion precursors (2), and homologous heterocycle core (both 1, and 2) (e.g., but not limited to: imidazole, triazole, tetrazole, benzimidazole, and benztriazole systems) can be formed.
  • homologous heterocycle core both 1, and 2 (e.g., but not limited to: imidazole, triazole, tetrazole, benzimidazole, and benztriazole systems) can be formed.
  • the protocol for the formation of azolium azolate salts via the reaction of two neutral components requires: zwitterionic cation precursor (1) with carboxylate group appended on the heterocycle core, and neutral heterocycle (2) with the pKa value lower then that of carboxylate group in cation precursor (1).
  • the reaction can be carried in any solvent systems (pure solvent or mixture of solvents) that allows for the dissolution of both components, or without solvents at all.
  • the reaction protocol comprises the following steps:
  • Proton transfer reactions protonation of carboxylate group in zwitterionic cation precursor (1); (step i) which is thermodynamically favored due to the difference in the pKa values of the zwitterionic salt carboxylate group and azolate anion (formed from deprotonation of anion precursor (2)).
  • step ii Decarboxylation of the system containing the protonated carboxylic acid group on the cation precursor in the intermediate (cationic part of compound 3) (step ii).
  • the decarboxyaltion may be performed in the presence of either polar solvents (e.g., but not limited to, DMSO, DMF, THF, trialkylamine, H 2 O) or heat (temp between 25° C.-150° C.).
  • the driving force for this conversion is the production of gaseous CO 2 which, upon removal from the reaction mixture, shifts the thermodynamic equilibrium in favor of product formation.
  • Examples of those ionic liquid compositions made utilizing above protocol include, but are not limited to, the mixture of at least two components of functionalized 5-, 6-membered, and bicyclic fused ring heterocyclic cation precursors and anion precursors containing 1, 2, 3, 4, or 5 atoms of nitrogen in the ring structure.
  • the cation precursors are neutral, zwitterionic species (neutral molecule that within itself contains both: cation and anion species) containing at least one cationic site (e.g., but not limited to, protonated or alkylated nitrogen atom) and one anionic site (carboxylate (COO—) group).
  • cationic site e.g., but not limited to, protonated or alkylated nitrogen atom
  • anionic site carboxylate (COO—) group
  • all carbon and nitrogen atoms in the ring structure can be ftunctionalized with additional substituents such as alkyl, allyl, aryl, nitro, nitrile, azido, hydroxyl, carboxylic acid, ester, amide, amine, aldehyde, ketone, epoxy, or functionalized alkyl and aryl groups (with any functional mentioned above).
  • the anion precursors are neutral, substituted, or not substituted, heterocyclic species containing at least one acidic proton site on any of the nitrogen atoms. This hydrogen atom will be utilized for the proton transfer reaction and consecutive decarboxylation reaction to form final azolium azolate product (4) as described in the protocol above.
  • all carbon and nitrogen atoms in the ring structure can be functionalized with additional substituents such as alkyl, allyl, aryl, nitro, nitrile, azido, hydroxyl, carboxylic acid, ester, amide, amine, aldehyde, ketone, epoxy, or ftunctionalized alkyl and aryl groups (with any functional mentioned above).
  • At least one of the R 1 -R 9 substituent groups can be a carboxylate anion group.
  • the remaining groups can be, independent of one another, not present, H, alkyl, alkenyl, alkynyl, allyl, aryl, nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl cyano, alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and alkoxy azido, isonitrile, carboxylic acid, ester, ether, CO 2 NR 8 2 , CO 2 NHR 8 , CO 2 NH 2 , amine, NHR 8 , NR 8 2 , ketone, aldehyde, epoxy, wherein R 8 is H, alkyl, alkenyl, alkynyl, allyl, aryl, carboxylic acid, ester,
  • At least one of the R 1 -R 9 substituent groups can be an H atom suitable for deprotonation to form stable heterocyclic azolate anion.
  • the remaining groups can be, independent of one another, not present, H, alkyl, alkenyl, alkynyl, allyl, aryl, nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl cyano, alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and alkoxy azido, isonitrile, carboxylic acid, ester, ether, CO2NR 8 2 , CO 2 NHR 8 , CO 2 NH 2 , amine, NHR 8 , NR 8 2 , ketone, aldehyde, or epoxy, wherein R 8 is H, alkyl, alkenyl, alkynyl, allyl, aryl, carboxylic acid, ester, ether, ketone, or aldehyde.
  • the disclosed ionic liquid compositions can have multiple functionalities or properties, each arising from the various ions that make up the ionic liquid, the disclosed ionic liquid compositions can be custom designed for numerous uses.
  • any combination of cations and anions, as disclosed herein can be made as long as the combination results in an ionic liquid as described herein. That is, any compound or active disclosed herein that has a given charge or can be made to have a given charge (the “first ion(s)”) can be combined with any other compound or active disclosed herein having a charge opposite to that of the first ion(s) or any compound that can be made to have a charge opposite to that of the first ion(s).
  • the ionic liquid compositions can have one type of cation and one type of anion, in a 1:1 relationship, so that the net charge of the ionic liquid is zero.
  • many of the ions disclosed herein can have multiple charges. Thus, when one ion having a multiple charge is used, more counterion(s) is needed, which will affect the ratio of the two ions. For example, if a cation having a plus 2 charge is used, then twice as much anion having a minus 1 charge is needed. If a cation having a plus 3 charge is used, then three times as much anion having a minus 1 charge is needed, and so on. While the particular ratio of ions will depend on the type of ion and their respective charges, the disclosed ionic liquids can have a cation to anion ratio of 1:1:, 2:1, 3:1, 4:1, 1:3, 2:1, 3:2, 2:3, and the like.
  • ionic liquid compositions disclosed herein can also have more than one different kind of cation and/or more than one different kind of anion.
  • the use of more than one kind of cation and/or anion can be particularly beneficial when one prepares an ionic liquid composition comprising two or more bioactive ions that are not desired to be in a 1:1 relationship.
  • ionic liquid compositions that contain varying effective amounts (or doses) of active substances can be prepared by varying the ratios of ions in the composition, as long as the total amount of cations is balanced by the total amount of anions.
  • an ionic liquid composition disclosed herein can contain one type of cation with a given property and two different anions (e.g., a first and second anion), each with another different property.
  • the resulting ionic liquid in this example will be 1 part cation, 0.5 part first anion, and 0.5 part second anion.
  • Another example of this adjustment in ion amounts can arise when one ion is particularly potent and thus dilution is desired.
  • a first cation that is particularly potent can be combined with a second (or third, forth, etc.) cation that is inert or has so other property that is desired.
  • the amount of the first cation is diluted by the other the cation(s).
  • many other such variations in the amount of cations and anions can be present in the disclosed methods and compositions.
  • specific ionic liquid compositions having particular combinations of cations and anions are disclosed herein, it is understood that the ratio of the particular ions can be varied or adjusted by adding other ions, so long as there is a balance of charge and the final composition is an ionic liquid.
  • the disclosed ionic liquid compositions have two or more ions with a bioactive property (e.g., pharmaceutical active ingredients, pesticidal actives, herbicidal actives, and the like), these compositions can be particularly desired because each of the active ingredients in the composition would have the same solubility and would dissolve together when formulated or administered. This can be particularly useful when overcoming formulation, solubility, bioavailability, size, and polymorphism issues. Further, when exact dosages of an active ingredient are needed, the active ingredient as an ion can be combined with a counterion that is innocuous or GRAS (generally recognized as safe).
  • GRAS generally recognized as safe
  • Saccharin acting as a weak acid, can form salts with basic active pharmaceutical ingredients including tertiary amines to form quaternary nitrogen atoms (Bhatt et al., Chem Comm, 2005, 1073-1075). Also known in the literature is N-hexadecylpyridinium saccharinate (CAS No. 7428-34-4).
  • ionic liquids include, but are not limited to, ionic liquids where any of the cations in the ionic liquid are aliphatic benzylalkyl ammonium cations (e.g., benzalkonium), dialiphatic dialkyl ammonium cations (e.g., didecyldimethylammonium), and aliphatic heteroaryl cations (e.g., hexadecylpyridinium) are combined with any of the anions of sulfacetamide, ibuprofen, and saccharinate.
  • aliphatic benzylalkyl ammonium cations e.g., benzalkonium
  • dialiphatic dialkyl ammonium cations e.g., didecyldimethylammonium
  • heteroaryl cations e.g., hexadecylpyridinium
  • Benzalkonium is used chiefly as an antiseptic and disinfectant. It is found in many over the counter and prescription eye products, disinfectants, shampoos, and deodorants. It also acts as a preservative in many pharmaceutical preparations. Didecyldimethylammonium (DDA) is used as an antiseptic and surfactant. N-hexadecylpyridinium (HEX) is used as an antiseptic agent alone or in combination with other drugs for oral and throat care. HEX is essentially nontoxic and can be applied to the skin or mucous membranes.
  • Sulfacetamide is used to control antibacterial activity and is sold under the trade name KLARONTM in the treatment of acne.
  • Ibuprofen is used as an anti-inflammatory and pain reliever.
  • Saccharinate is used as a sweetener.
  • Suitable ionic liquids include, but are not limited to, benzalkonium sulfacetamide (BA-sulfacetamide), didecyldimethylammonium sulfacetamide (DDA-sulfacetamide), N-hexadecylpyridinium sulfacetamide (HEX-sulfacetamide), benzalkonium ibuprofen (BA-ibuprofen), didecyldimethylammonium ibuprofen (DDA-ibuprofen), N-hexadecylpyridinium ibuprofen (HEX-ibuprofen), and benzalkonium acesulfamate, didecyldimethylammonium acesulfamate, N-hexadecylpyridinium acesulfamate, and benzalkonium saccharinate (BA-SAC).
  • BA-sulfacetamide benzalkonium sulface
  • an ion that is antiseptic can be combined with an ion that is antibacterial agent.
  • an ionic liquid can comprise benzalkonium and sulfacetamide, which is shown in formula X.
  • Another example is the combination of didecyldimethylammonium sulfacetamide, which is shown in formula XI.
  • Still another example is the combination of N-hexadecylpyridinium sulfacetamide, which is shown in formula XII.
  • Such antiseptic/antibacterial compositions can be used in the treatment of wounds, for example, wounds near the scalp where a composition with both disinfectant and antibacterial properties is desirable.
  • Such compounds could also be used for skin care, e.g., to treat acne.
  • an ion that is antibacterial can be combined with an anti-inflammatory and/or pain reliever.
  • Such compositions can be used as a disinfectant and for pain relief.
  • an ionic liquid can comprise benzalkonium and ibuprofen, which is shown in formula XIII.
  • the ionic liquid composition can comprise didecyldimethylammonium and ibuprofen, which is shown in formula XIV.
  • the ionic liquid composition can comprise N-hexadecylpyridinium and ibuprofen, which is shown in formula XV.
  • an ion that is an antibacterial can be combined with an ion that is a sweetener.
  • Such compositions can be used to improve the taste of medicines and hygiene products and can be used in, for example, toothpaste, and children's medicine.
  • Some specific examples of such ionic liquids is prepared by combining the antibacterial agents benzalkonium, didecyldimethylammonium, or N-hexadecylpyridinium and the sweetener acesulfamate, as shown in formulas XVI, XVII, and XVIII, respectively.
  • antibacterial agents benzalkonium, didecyldimethylammonium, and N-hexadecylpyridinium can also be combined with the sweetener saccharinate, as shown in formulas XIV, XX, and XXI, respectively.
  • the ionic liquid composition can comprise an ion that is an antibacterial agent with an ion that is a UV-blocker, such as trans-cinnamate.
  • a UV-blocker such as trans-cinnamate.
  • Such compositions can be used as disinfectants and for protection against UV radiation, as would be desirable for treating wounds exposed to the Sun's radiation.
  • Specific examples of such composition include, but are not limited to, compositions where the cation is an antibacterial agent such as benzalkonium, didecyldimethylanimonium, or N-hexadecylpyridinium, and the anion is trans-cinnamate, as is shown in formulas XXII, XXIII, and XXIV respectively.
  • the disclosed ionic liquids can comprise an ion that is an antibacterial and an ion that can provide wetting and controls reaction rate, particle size, viscosity, polymer molecular weight, and stability in emulsion polymerization systems, e.g., sodium dihexylsulfosuccinate (e.g., Colawet MA-80 from Colonial Chemicals, South Pittsburg, Tenn.)).
  • an ion that is an antibacterial and an ion that can provide wetting and controls reaction rate, particle size, viscosity, polymer molecular weight, and stability in emulsion polymerization systems, e.g., sodium dihexylsulfosuccinate (e.g., Colawet MA-80 from Colonial Chemicals, South Pittsburg, Tenn.)).
  • compositions include, but are not limited to, compositions where the cation is an antibacterial agent such as benzalkonium, didecyldimethylammonium, or n-hexadecylpyridinium, and the anion is Colawet MA-80, as shown in formulas XXV, XXVI, and XXVII, respectively.
  • an antibacterial agent such as benzalkonium, didecyldimethylammonium, or n-hexadecylpyridinium
  • the anion is Colawet MA-80, as shown in formulas XXV, XXVI, and XXVII, respectively.
  • the disclosed ionic liquid compositions can comprise an ion that is antibacterial and an ion that is a food colorant.
  • ionic liquid compositions include, but are not limited to, compositions where the cation is an antibacterial agent such as benzalkonium, didecyldimethylammonium, or N-hexadecylpyridinium, and the anion is Fast Green FCF, an FDA approved color additive that provides a sea green hue and is used in products such as beverages, puddings, ice cream, sherbet, cherries, confections, baked goods, and dairy products.
  • Other food coloring anions which are well known in the art, can be used as well.
  • the disclosed ionic liquid compositions can comprise a cation that is an antibacterial and an anion that is an antibacterial.
  • the cationic antibacterial agents disclosed herein can be combined with the anionic piperacillin, which is an extended-spectrum penicillin. Piperacillin is primarily used in the treatment of susceptible infections such as septicemia, acute and chronic respiratory tract infections, skin and soft tissue infections, and urinary tract infections.
  • the disclosed ionic liquid compositions are those where the anion is benzoate and the cation comprises one or more of (2-acetoxyethyl)-dodecyloxymethyldimethylammonium, (2-acetoxyethyl)-heptyloxymethyldimethylammonium, (2-hydroxyethyl)-cyclododecyloxymethyldimethylammonium, or (2-hydroxyethyl)-dimethylundecyloxymethylammonium.
  • ionic liquid compositions are those where the cation comprises benzalkonium, didecyldimethylammonium, or N-hexadecylpyridinium and the anion comprises one or more of acesulfamate, benzoate, colawet ma-80, fast green FCF, ibuprofen, penicillin G, piperacillin, saccharinate, salicylate, salicylate, sulfacetamide, trans-cinnamate, sulfathiazole, thimerosal, valproic acid, mepenzolate, docusate.
  • the cation comprises benzalkonium, didecyldimethylammonium, or N-hexadecylpyridinium
  • the anion comprises one or more of acesulfamate, benzoate, colawet ma-80, fast green FCF, ibuprofen, penicillin G, piperacillin, saccharinate, salicylate, salicylate
  • benzalkonium is combined with mepenzolate and docusate in a 1:1:2 ratio, a 2:1:3 ratio, or a 1:2:3 ration. In another example, benzalkonium is combined with sulfathiazole and saccharinate in a 2:1:1 ratio.
  • ionic liquid compositions are those where the cation is didecyldimethylammonium and the anion comprises one or more of saccharinate, (S)-6-methoxy- ⁇ -methyl-2-naphthaleneacetate, 2-[(2,6-dichlorophenyl)amino]-benzeneacetate, 2-[(2,6-dichlorophenyl)amino]-benzeneacetate, 2-acetoxybenzoate, acesulfamate, benzoate, colawet ma-80, fast green FCF, ibuprofen, mandelate, N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-glutamate, nicotinate, penicillin G, piperacillin, p-toluenesulfonate, salicylate, sulfacetamide, or trans-
  • ionic liquid compositions are those where the cation is hexadecylpyridinium and the anion comprises one or more of colawet ma-80, fast green FCF, penicillin G, piperacillin, or sulfacetamide.
  • the disclosed ionic liquid compositions are those where the cation is hexadecylpyridinium and the anion comprises one or more of clofencet, fluroxypyr, diflufenzopyr, mesosulfuron, prohexadione, pantoprazole, risedronate, losartan, rabeprazole, fosinopril, ceftioxone, atorvastatin, pravastatin, alendronate, montelukast, tazobactam, Allura Red AC, tartrazine, indigotine, erythrosine, or Sunset Yellow.
  • ionic liquid compositions are those where the cation is didecyldimethylamrnonium and the anion comprises one or more of clofencet, fluroxypyr, diflufenzopyr, mesosulfuron, prohexadione, pantoprazole, risedronate, losartan, rabeprazole, fosinopril, ceftioxone, atorvastatin, pravastatin, alendronate, montelukast, tazobactam, Allura Red AC, tartrazine, indigotine, erythrosine, or Sunset Yelow.
  • the anion comprises one or more of clofencet, fluroxypyr, diflufenzopyr, mesosulfuron, prohexadione, pantoprazole, risedronate, losartan, rabeprazole, fosinopril, ceftioxone, atorvastatin, pravastatin,
  • ionic liquid compositions are those where the cation is benzalkonium and the anion comprises one or more of clofencet, fluroxypyr, diflufenzopyr, mesosulfuron, prohexadione, pantoprazole, risedronate, losartan, rabeprazole, fosinopril, ceftioxone, atorvastatin, pravastatin, alendronate, montelukast, tazobactam, Allura Red AC, tartrazine, indigotine, erythrosine, or Sunset Yellow.
  • the anion comprises one or more of clofencet, fluroxypyr, diflufenzopyr, mesosulfuron, prohexadione, pantoprazole, risedronate, losartan, rabeprazole, fosinopril, ceftioxone, atorvastatin, pravastatin, alendronate, monteluka
  • compositions docusate lidocaine, miconazole/econazole docusate, streptomycin docusate, and isoniazide docusate.
  • Docusate combined with any of the cationic 5 and 6 membered quaternary ammonium ring compounds disclosed herein are also contemplated herein.
  • Still further examples include a cation that is an anticholinergic like mepenzolate and the anion is docusate.
  • Itraconazole which inhibits cytochrome p540 oxidase mediated snthesis of ergosterol.
  • Itraconazole is a 1:1:1 racemic mixture offourdiastereomers comprising 2 enantiomeric pairs. Generally, it has poor adsorption especially when givenin capsule form. This is though to occur because 99.8% of the drug becomes bound to proteins in the body. It has been shown that absorption is improvedwit acid as the pKa is 3.70; therefore, it is recommended that this drug be taken with orange juice.
  • the compound is insoluble in water, slightly soluble in alcohol, and freely soluble in dichloromethane. This compound can be combined with any of the anions disclosed herein, for example, sulfacetamide, colawet MA-80, and docusate.
  • a prodrug is a pharmacologically inactive compound that is converted to an active drug by a metabolic biotransformation. Prodrugs are used when there are concerns regarding a drugs solubility, absorption and distribution, site specificity, stability, prolonged release, toxicity, patient acceptability, and formulation concerns. Carrier linked prodrugs are also contemplated.
  • a carrier linked prodrug is a compound thatcontains an active drug linked to a carrier group that can be removed enzymatically, such as an ester, which is hydrolyzed to an active carboxylicacid containing drug.
  • Other types of carrier linkages include alcohols and carboxylic acids, amines, and carbonyl compounds.
  • mutual prodrugs which comprise two drugs attached to each other where one is the carrier for the other and vice versa.
  • compositions comprising lidocaine and silver.
  • This composition has a component that is functional for topical anesthesia (lidocaine) with one Ag+ that has antimicrobial properties.
  • This can be used in conjunction with lidocaine docusate, as described herein, to create ointments or bandage materials that are capable of providing a palliative effect as well as suppression of microorganism growth.
  • silver docusate can be prepared, which can provide a lipophilic salt of silver that would be soluble in lidocaine docusate, other ILs, or even non-IL votingme bases, for end-use as a topical antimicrobial agent.
  • compositions comprising ranitidine and docusate.
  • This compound can generate a rather lipophilic, hydrophobic version of ranitidine, which would be both non-crystalline and sufficiently sluggish in its rate of dissolution against biofluids that it could serve as a slow-release form of the drug.
  • Lidocain docusate is another example contemplated herein.
  • the disclosed ionic liquid compositions can be prepared by combining one or more kinds of cations or cation precursors with one or more kinds of anions or anion precursor.
  • Providing of the particular ions is largely based on the identifying desired properties of the ion (e.g., its charge and whether it has a particular bioactivity that is desired to be present in the resulting ionic liquid).
  • Methods of identifying suitable ions are disclosed herein, for example, by considering the chemical structure and charge of the compounds and whether the ion combination will produce an ionic liquid.
  • an ion that minimizes coulombic interactions by diffusing its charge over several atoms in the ion is identified.
  • An example of this is the alkylheteroaryl cations disclosed herein where the positive charge is spread over the atoms of the heteroaryl ring.
  • a weakly coordinating counterion which also delocalizes charge over several atoms, is chosen.
  • more-complex and higher molecular weight cations and anions have a greater number of intermolecular contacts, which serves to raise melting point and increase the viscosity of the ionic liquid composition.
  • molecular asymmetry can be particularly desired. Low-symmetry cations and anions typically reduce packing efficiency in the crystalline state and lower melting points.
  • the cation should not be more nucleophilic than the neutral form of the cation. If this is the case, then suitable anions can be selected by considering their pKa. For example, by utilizing the pKa of acid functionalized compounds and the pKb of base functionalized compounds, one can combine the neutral species of acids and bases into one neutral compound possessing the functions of both compounds. To successfully produce an ionic liquid by this method, the pKa or pKb of compound A should be different by approximately 5 orders of magnitude from the pKa or pKb of compound B. This insures that the acidity or basicity at that hydrogen is sufficient to remove or add a hydrogen at that position. This will then produce an anion on the acidic compound and a cation on the basic compound.
  • One method for identifying a suitable ion combination for preparing an ionic liquid as disclosed herein is by computer program. It is also possible to use a computer to select various cation and anion combinations.
  • the program called ERWINTM sold by Computer Associates (Islandia, N.Y.), can be used.
  • This computer program is comprised of two models: a forward model which predicts the melting points and drug delivery rates of a formulation of ionic liquids, and a backwards model will allow the user to select which type of pharmaceutical agents that are desired along with liquid range and delivery rates and the program will give all the formulations which meet these criterion.
  • FIG. 3 illustrates how the two models interact.
  • CODESSATM Semichem, Inc. Shawnee Mission, Kans.
  • CODESSATM Semichem, Inc. Shawnee Mission, Kans.
  • the researcher would feed this request into the program and all of the formulations meeting these requirements and being composed entirely of a balanced ionic liquid formula would be suggested to the researcher.
  • the ions can be combined to form the disclosed ionic liquids.
  • a salt of the desired cation e.g., a halide salt
  • a salt of the desired anion e.g., transition metal, like Ag, salt, Group I or II metal salt, or ammonium salt.
  • Such reactions can be performed with many different types of salts; and (2) an acid-base neutralization reaction.
  • Another method for forming the disclosed ionic liquid compostions involves a reaction between a salt of a desired cation, say CationX where X is an appropriate balancing anion (including but not necessarily a halide), and an acid to yield the ionic liquid and HX byproduct.
  • a salt of a desired cation say CationX where X is an appropriate balancing anion (including but not necessarily a halide)
  • the disclosed ionic liquid compositions can be formed by reacting a salt of a desired anion, say YAnion where Y is an appropaite balancing cation, with a base to yield the ionic liquid and Ybase byproduct.
  • bioactive compounds e.g., pharmaceutical actives, pesticidal actives, herbicidal actives, etc.
  • energetic compounds disclosed herein are cationic or can be made cationic, the identification of which can be made by simple inspection of the chemical structure as disclosed herein.
  • many of these compounds are commercially available as their halide salts or can be converted to their halide salts by reactions with acids (e.g., HF, HCl, HBr, or HI) or by treating a halogenated compound with a nucleophile such as an amine.
  • acids e.g., HF, HCl, HBr, or HI
  • anions disclosed herein are commercially available as metal salts, Group I or II metal salts, or ammonium salts.
  • Ionic liquids which are immiscible with water are often conveniently prepared by the combination of aqueous solutions of two precursor salts, each of which contains one of the two requisite ions of the targeted ionic liquids.
  • the desired salt forms a separate phase from the aqueous admixture.
  • Such phases are readily washed free of byproduct salts with additional water, and may subsequently subjected to other procedures (e.g., as disclosed in the Examples) to separate them from non-water soluble impurities.
  • it is also possible to prepare water immiscible ionic liquids by the addition to a neutral amine-containing compound (e.g., an active pharmaceutical ingredient) of an acid such as aqueous HTf 2 N.
  • a neutral amine-containing compound e.g., an active pharmaceutical ingredient
  • Certain Tf 2 N ⁇ salts of N—H containing cations are known to be water-immiscible.
  • ionic liquids can be purified by techniques familiar to those skilled in the art of organic and inorganic synthesis, with the notable exception of purification by distillation of the ionic liquid.
  • One particularly useful approach is the use of conventional or reverse-phase chromatography to separate the salt of interest from other ionic or non-ionic materials, followed by the separation of the ionic liquid from the eluting solvent, commonly by evaporation of the latter.
  • ionic liquids can be purified by crystallization or thermal zone crystallization at appropriate conditions of temperature and pressure.
  • Such techniques can include the use of a solvent from which the ionic liquid can be crystallized at an appropriate temperature.
  • Other purification techniques include exchange column chromatography and supercritical CO 2 fluid extraction.
  • the disclosed ionic liquid compositions have many uses.
  • the disclosed ionic liquid compositions can be used to allow fine tuning and control of the rate of dissolution, solubility, and bioavailability, to allow control over physical properties and mechanical strength, to improve homogenous dosing, and to allow easier formulations.
  • the disclosed ionic liquid compositions also make having compositions with additional functionality possible.
  • One notable advantage of the disclosed ionic liquid compositions is that they can be used to alleviate the problems associated with polymorphism.
  • a compound subject to polymorphism can be used as an ion in the disclosed ionic liquid compositions. In this way, the compound will become part of the ionic liquid composition and thus not a crystalline solid that is subject to polymorphism.
  • polymorphism can be prevented by dissolving the compound in the ionic liquid.
  • An advantage of having ionic liquid compositions is that the solubility and bioavailability can be known and predicted. This allows homogeneous and predictable dosing and tableting.
  • the disclosed ionic liquid compositions can be used to alleviate side effects associated with various compounds.
  • the disclosed ionic liquid compositions can contain an ion from a drug known to have an undesirable side effect along with a counterion that is a drug known to alleviate or counteract that side effect.
  • An example of this is an ionic liquid composition that comprises the ions of morphine and docusate.
  • Such a composition can be used to treat pain due to the presence of morphine and relieve constipation due to the presence of docusate.
  • many pharmaceuticals are known to cause constipation, and ionic liquids of these compounds with docusate or other laxatives are contemplated herein.
  • any use that exists for one or more of the ionic components in the ionic liquid is also a use for the ionic liquid composition itself.
  • the ionic liquid composition can also be used for the same indication as the pharmaceutical active.
  • many of the compounds disclosed herein as being suitable ions for the disclosed ionic liquids have already been proven to be effective alone or in some other preparation. Many of the disclosed compounds are even FDA approved. When such compounds are prepared as part of an ionic liquid, as disclosed herein, they can still maintain their efficacy, and can even have their efficacy enhanced by being part of the ionic liquid composition.
  • an ionic liquid having a pharmaceutical active as one or more of its cations or anions when administered to a subject, the pharmaceutical active will dissociate from the ionic liquid and be available to the subject in the same way as had a solid form (e.g., tablet) or solution of the pharmaceutical active been administered.
  • a solid form e.g., tablet
  • This effect is also observed for the antibacterial, antiviral, pesticidal, herbicidal, nutritional, food additives and other compounds and actives disclosed herein.
  • ionic liquid compositions include the dissolution of the ionic liquid into liquid bandages.
  • Liquid bandages are available from commercial suppliers such as Johnson and Johnson.
  • the various ions in the ionic liquid e.g., antiinfective, steroidal, anesthetic, etc. ions
  • the disclosed ionic liquids can be coated onto a cellulosic bandage (e.g., a gauze or dressing).
  • a cellulosic bandage e.g., a gauze or dressing.
  • the bandage will contain the various active ions of the ionic liquid along with their associated functionality.
  • the disclosed ionic liquids can be melted by a consumer or physician (e.g., with hot water) and then “painted” onto an area of interest. It would then cool as a thin, solid coating of the ionic liquid. This use can provide a slow release form of the API in the ionic liquid or impart a desirable barrier on the area of interest.
  • the disclosed ionic liquid compositions can be used to treat a subject diagnosed with, for example, endocrine disorders, diabetes, infertility, hormone deficiencies, osteoporosis, ophthalmological disorders, neurodegenerative disorders, Alzheimer's disease, dementia, Parkinson's disease, multiple sclerosis, Huntington's disease, cardiovascular disorders, atherosclerosis, hyper-coagulable states, hypo-coagulable states, coronary disease, cerebrovascular events, metabolic disorders, obesity, vitamin deficiencies, renal disorders, renal failure, haematological disorders, anemia of different entities, immunologic and rheumatologic disorders, autoimmune diseases, immune deficiencies, infectious diseases, viral infections, bacterial infections, fungal infections, parasitic infections, neoplastic diseases, multi-factorial disorders, impotence, chronic pain, depression, and different fibrosis states.
  • endocrine disorders for example, endocrine disorders, diabetes, infertility, hormone deficiencies, osteoporosis, ophthalmological disorders, neurodegenerative disorders, Alzheimer's disease, dementia, Parkinson's
  • the ionic liquid compositions disclosed herein that contain ionic pesticidal and herbicidal actives can be used in the same way as the actives themselves.
  • any use contemplated for a pesticidal and herbicidal active is contemplated herein for an ionic liquid composition containing that active.
  • the disclosed ionic liquid compositions are liquid at a given temperature, they avoid problems associated with polymorphism. For example, one can vary the individual ions and the combination of ions to fine tune the characteristics of the compositions, thus obtaining a composition with desired properties (e.g., better dissolution, solubility, or bioavailability). This can lead to easier dosing and formulating of the actives in the compositions.
  • desired properties e.g., better dissolution, solubility, or bioavailability
  • ionic liquid compositions that comprise administering an effective amount of at least one ionic liquid composition as disclosed herein.
  • effective amount of a compound as provided herein is meant a nontoxic but sufficient amount to provide the desired result.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease that is being treated, the particular compound used, its mode of administration, and the like. Thus, it is not possible to specify an exact “effective amount.” However, an appropriate effective amount can be determined by one of ordinary skill in the art using only routine experimentation. The dose, schedule of doses, and route of administration can be varied.
  • the efficacy of administration of a particular dose of the ionic liquid compositions according to the methods described herein can be determined by evaluating the particular aspects of the medical history, signs, symptoms, and objective laboratory tests that are known to be useful in evaluating the status of a subject in need of attention for the treatment of a disease and/or condition. These signs, symptoms, and objective laboratory tests will vary, depending upon the particular disease or condition being treated or prevented, as will be known to any clinician who treats such patients or a researcher conducting experimentation in this field.
  • a subject's physical condition is shown to be improved, (2) the progression of the disease or condition is shown to be stabilized, or slowed, or reversed, or (3) the need for other medications for treating the disease or condition is lessened or obviated, then a particular treatment regimen will be considered efficacious.
  • the disclosed ionic liquid compositions can be used therapeutically as neat ionic liquids.
  • the disclosed ionic liquids can be used in combination with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical formulation in which it is contained.
  • the carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art.
  • many of the disclosed ionic liquids can be used prophylactically, i.e., as a preventative agent, either neat or with a pharmaceutically acceptable carrier.
  • the ionic liquid compositions disclosed herein can be conveniently formulated into pharmaceutical compositions composed of neat ionic liquid or in association with a pharmaceutically acceptable carrier. See e.g., Remington's Pharmaceutical Sciences , latest edition, by E. W. Martin Mack Pub. Co., Easton, Pa., which discloses typical carriers and conventional methods of preparing pharmaceutical compositions that can be used in conjunction with the preparation of formulations of the compounds described herein and which is incorporated by reference herein.
  • compositions most typically, would be standard carriers for administration of compositions to humans and non-humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. Other compounds can be administered according to standard procedures used by those skilled in the art.
  • pharmaceutical compositions can also include one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like.
  • Examples of pharmaceutically-acceptable carriers include, but are not limited to, saline, Ringer's solution and dextrose solution.
  • the pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5.
  • Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the disclosed compounds, which matrices are in the form of shaped articles, e.g., films, liposomes, microparticles, or microcapsules. It will be apparent to those persons skilled in the art that certain carriers can be more preferable depending upon, for instance, the route of administration and concentration of composition being administered. Other compounds can be administered according to standard procedures used by those skilled in the art.
  • compositions can include additional carriers, as well as thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the compounds disclosed herein.
  • Pharmaceutical formulations can also include one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like.
  • the pharmaceutical formulation can be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topically (including ophthalmically, vaginally, rectally, intranasally), orally, by inhalation, or parenterally, for example by intravenous drip, subcutaneous, intraperitoneal or intramuscular injection.
  • the disclosed compounds can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally as is described more fully elsewhere herein.
  • a delivery device to deliver an ionic liquid composition as disclosed herein to a subject.
  • methods for delivering an ionic liquid composition to a subject by administering to the subject any of the nutritional supplements, pharmaceutical formulations, controlled release vehicles, delivery and/or devices.
  • compositions described herein can be administered to the subject in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated.
  • a composition described herein can be administered as an ophthalmic solution and/or ointment to the surface of the eye.
  • a compound or pharmaceutical composition can be administered to a subject vaginally, rectally, intranasally, orally, by inhalation, or parenterally, for example, by intradermal, subcutaneous, intramuscular, intraperitoneal, intrarectal, intraarterial, intralymphatic, intravenous, intrathecal and intratracheal routes. Parenteral administration, if used, is generally characterized by injection.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • a more recently revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained.
  • an ionic liquid composition such as lidocaine docusate is contacted to the skin of a subject to provide an anesthetic effect.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions which can also contain buffers, diluents and other suitable additives.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives, such as antimicrobials, anti-oxidants, chelating agents, and inert gases and the like, can also be present.
  • Formulations for topical administration can include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • the disclosed ionic liquid compositions having hydrophobic ions can be particularly useful in such applications because they can adhere to the surface longer when exposed to water or other fluids than would a similar hydrophilic salt.
  • ionic liquids comprising disinfectant, herbicide, or pesticide ions and hydrophobic counterions can be expected to resist erosion from rainfall.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like can be necessary or desirable.
  • ionic liquid compositions containing pharmaceutical actives formulated with highly hydrophobic anions or cations can have longer durations of adhesion when exposed to water or other fluids than would similar hydrophilic salts applied in these environments. This would be particularly beneficial for sun screens. It should also be noted that disinfectants, pesticides, or herbicides applied to plant leaves can be less prone to be lost by rain even if it follows application.
  • an effective amount of the composition can be contacted (i.e., administered) to any surface that has bacteria.
  • an effective amount of the composition can be administered to an area to control pests.
  • an effective amount of the composition can be administered to an area to control plants.
  • Techniques for contacting such surfaces and areas with the disclosed ionic liquid compositions can include, spraying, coating, dipping, immersing, or pouring the composition into or onto the surface or area. The precise technique will depend on such factors as the type and amount of infestation or contamination, the size of the area, the amount of composition needed, preference, cost and the like.
  • any of the compounds described herein can be incorporated into a delivery device.
  • delivery devices include, but are not limited to, microcapsules, microspheres, nanospheres or nanoparticles, liposomes, noisome, nanoerythrosome, solid-liquid nanoparticles, gels, gel capsules, tablets, lotions, creams, sprays, emulsions, or powders.
  • Other examples of delivery devices that are suitable for non-oral administration include pulmospheres. Examples of particular delivery devices usefuil herein are described below.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the disclosed compositions in liposome form can contain, in addition to a compound disclosed herein, stabilizers, preservatives, excipients, and the like. Examples of suitable lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods of forming liposomes are known in the art.
  • the liposomes can be cationic liposomes (e.g., DOTMA, DOPE, DC cholesterol) or anionic liposomes. Liposomes can further comprise proteins to facilitate targeting a particular cell, if desired. Administration of a composition comprising a compound and a cationic liposome can be administered to the blood afferent to a target organ or inhaled into the respiratory tract to target cells of the respiratory tract. Regarding liposomes, see, e.g., Brigham, et al., Am J Resp Cell Mol Biol 1:95-100, 1989; Felgner, et al., Proc Natl Acad Sci USA 84:7413-7, 1987; and U.S. Pat. No.
  • liposomes delivery can be via a liposome using commercially available liposome preparations such as LIPOFECTIN, LIPOFECTAMINE (GIBCO-BRL, Inc., Gaithersburg, Md.), SUPERFECT (Qiagen, Inc. Hilden, Germany) and TRANSFECTAM (Promega Biotec, Inc., Madison, Wis.), as well as other liposomes developed according to procedures standard in the art. Liposomes where the diffusion of the compound or delivery of the compound from the liposome is designed for a specific rate or dosage can also be used.
  • niosomes are delivery devices that can be used to deliver the compositions disclosed herein.
  • noisysomes are multilamellar or unilamellar vesicles involving non-ionic surfactants. An aqueous solution of solute is enclosed by a bilayer resulting from the organization of surfactant macromolecules.
  • noisomes are used in targeted delivery of, for example, anticancer drugs, including methotrexate, doxorubicin, and immunoadjuvants. They are generally understood to be different from transferosomes, vesicles prepared from amphiphilic carbohydrate and amino group containing polymers, e.g., chitosan.
  • Nanoerythrosomes are delivery devices that can be used to deliver the compositions disclosed herein.
  • Nanoerythrosomes are nano-vesicles made of red blood cells via dialysis through filters of defined pore size. These vesicles can be loaded with a diverse array of biologically active molecules, including proteins and the compositions disclosed herein. They generally serve as ideal carriers for antineoplastic agents like bleomycin, actinomycin D, but can be used for steroids, other lipids, etc.
  • Artificial red blood cells are further delivery devices that can be used to deliver the compositions disclosed herein. Artificial red blood cells can be generated by interfacial polymerization and complex emulsion methods. Generally, the “cell” wall is made of polyphtaloyl L-lysine polymer/polystyrene and the core is made of a hemoglobin solution from sheep hemolysate. Hemoglobin loaded microspheres typically have particle sizes of from about 1 to about 10 mm. Their size, flexibility, and oxygen carrying capacity is similar to red blood cells.
  • Solid-lipid nanoparticles are other delivery devices that can be used to deliver the compositions disclosed herein.
  • Solid-lipid nanoparticles are nanoparticles, which are dispersed in an aqueous surfactant solution. They are comprised of a solid hydrophobic core having a monolayer of a phospholipid coating and are usually prepared by high-pressure homogenization techniques.
  • Immunomodulating complexes are examples of solid-lipid nanoparticles. They are cage-like 40 nm supramolecular assemblies comprising of phospholipid, cholesterol, and hydrophobic antigens and are used mostly as immunoadjuvants. For instance, ISCOMs are used to prolong blood-plasma levels of subcutaneously injected cyclosporine.
  • Microspheres and micro-capsules are yet other delivery devices that can be used to deliver the compositions disclosed herein.
  • microspheres and micro-capsules typically do not have an aqueous core but a solid polymer matrix or membrane.
  • These delivery devices are obtained by controlled precipitation of polymers, chemical cross-linking of soluble polymers, and interfacial polymerization of two monomers or high-pressure homogenization techniques.
  • the encapsulated compound is gradually released from the depot by erosion or diffusion from the particles.
  • Poly(lactide co-glycolide (PLGA) microspheres are currently used as monthly and three monthly dosage forms in the treatment of advanced prostrate cancer, endometriosis, and other hormone responsive conditions.
  • Leuprolide an LHRH superagonist, was incorporated into a variety of PLGA matrices using a solvent extraction/evaporation method. As noted, all of these delivery devices can be used in the methods disclosed herein.
  • Pulmospheres are still other examples of delivery devices that can be used herein. Pulmospheres are hollow porous particles with a low density (less than about 0.1 gm/mL). Pulmospheres typically have excellent re-dispersibility and are usually prepared by supercritical fluid condensation technology. Co-spray-drying with certain matrices, such as carbohydrates, human serum albumin, etc., can improve the stability of proteins and peptides (e.g., insulin) and other biomolecules for pulmonary delivery. This type of delivery could be also accomplished with micro-emulsions and lipid emulsions, which are ultra fine, thin, transparent oil-in-water (o/w) emulsions formed spontaneously with no significant input of mechanical energy.
  • matrices such as carbohydrates, human serum albumin, etc.
  • an emulsion can be prepared at a temperature, which should be higher than the phase inversion temperature of the system.
  • the emulsion is of water-in-oil (w/o) type and as it cools at the phase inversion temperature, this emulsion is inverted to become o/w. Due to their very small inner phase, they are extremely stable and used for sustained release of steroids and vaccines.
  • Lipid emulsions comprise a neutral lipid core (i.e., triglycerides) stabilized by a monolayer of amphiphilic lipid (i.e., phospholipid) using surfactants like egg lecithin triglycerides and miglyol. They are suitable for passive and active targeting.
  • the disclosed ionic liquid compositions can be formulated as part of a controlled release vehicle.
  • a controlled release vehicle for example, microspheres and microcapsules, implants, and the like containing liquid bioactive agents are well known, as are methods for their preparation. As such, these methods can be used with the disclosed ionic liquid compositions to produce controlled release vehicles that can release the disclosed ionic liquid composition with a desired release profile.
  • a glass ionic liquid composition can be cooled to form a pill. That is, glasses are “cast-able” above their glass transition temperature (T g ) into shapes with specific surface areas, allowing predictable release/pharmacokinetic properties. Below T g , these disclosed glass ionic liquid composition can be milled into specific shapes and sizes. Alternatively, the disclosed ionic liquid compositions can be tableted as liquids that upon cooling form glasses. Such a method can allow the homogeneous distribution of a pharmaceutical active into the tablet.
  • a particular example includes ionic liquid compositions that are in the glass form but melt at or slightly above body temperature.
  • Such compositions can allow formulation as a solid, but have known solubility, bioavailability, etc. as a liquid.
  • These compositions can have uses in, for example, bandages, patches, or wound dressings.
  • glass compositions that “melt” slightly above room temperature can be “melted” by a consumer or physician with, e.g., hot water or body heat, and “painted” onto an area of interest (infected area).
  • Cooling of the composition can then provide a thin, solid coating of material which is both a slow release form of an active ingredient ion (e.g., anti-infective, steroid, anesthetic, or combination thereof), plus serve as a physical barrier.
  • an active ingredient ion e.g., anti-infective, steroid, anesthetic, or combination thereof
  • the disclosed ionic liquids can be used as carriers for other active compounds, many of which are disclosed herein.
  • prodrugs, ionic and neutral active molecules can be dissolved in the disclosed ionic liquid compositions.
  • Further methods of administration can include incorporating the disclosed ionic liquid composition in to a food stuff or beverage, which can be ingested by a subject.
  • the disclosed ionic liquids can also be encapsulated in a polymer matrix by methods known in the art.
  • the disclosed ionic liquid compositions can be dissolved in a suitable solvent or carrier as are disclosed herein.
  • This method can enhance the delivery of one or more active ions in the ionic liquid. Further, as is disclosed herein, this method can create a synergistic effect among the various ions present. While not wishing to be bound by theory, the dissociate coefficient of various ions in an ionic liquid can be different in different solvents. Thus, ions in an ionic liquid can dissociate freely in one solvent and cluster in another. This phenomenon can be utilized to provide formulations of compound that are difficult to deliver (e.g., increase the water solubility of steroids).
  • compounds can be formed into an ionic liquid, as described herien, and then dissolved in a suitable solvent to provide an easily deliverable solution.
  • a synertistic effect can be observed upon administration to a subject, when ions cluster and act together, rather than independently.
  • Synthesized benzalkonium saccharinate was obtained with 98% yield. It is very sweet in taste. Obtained wax is poorly dissolvable in cold and warm water. Crystalline benzalkonium saccharinate, with the melting point of 80-82° C., was obtained form the mixture of dry (no water) acetone and diethylether in the volume ratio of 10:1.
  • Staphylococcus aureus ATCC 6538 Staphylococcus aureus ATCC 6538 , Enterococcus faecium ATCC 49474 , Escherichia coli ATCC 25922 and fungi Candida albicans ATCC 10231.
  • Microbiological activity tests were performed using dissolution method. Determinations were performed on liquid base (background): Mueller-Hinton for bacteria and Sabouraud for fungi. Starting solution had the concentration of 1 g/cm 3 . From this solution, all other solutions (lower concentrations) were prepared. To those solutions, 0.1 cm 3 of the suspensions of standard microorganisms at a concentration of 10 6 cfu cm 3 were added. The samples with bacteria were incubated for 24 h at the temperature of 37° C., and with fungi there were incubated for 48 h at the temperature of 22° C.
  • Minimal Inhibitory Concentration minimal concentration of the investigated compound at which the growth of the microorganisms is stopped (visually), was specified (recorded) for every sample.
  • MBC Minimum Bactericidal Concentration, additionally to each solution the 10 ⁇ 6 cm 3 of the inactivator was added on the base (background) (0.3% lecithin, 3% polysorbate 80 and 0.1% L-cysteine).
  • the samples with bacteria were incubated for 48 h in the temperature of 37° C.
  • the fungi samples were incubated for 5 days at the temperature of 22° C.
  • MBC values were defined (specified) as the concentration at which the level of the reduction of the microorganisms was not lower than 99.99%.
  • Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring.
  • Didceyldimethylammonium bromide (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring.
  • Sodium sulfacetamide (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride anions was monitored by silver nitrate test.
  • Hexadecylpyridinium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring.
  • Sodium sulfacetanide (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride anions was monitored by silver nitrate test.
  • Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring.
  • Didecyldimethylammonium bromide (0.001 mol) was dissolved in 50 mL of hot distilled water.
  • trans-Cinnamic acid (0.001 mol) was added to the didecyldimethylammonium solution.
  • the reaction solution was stirred at 90° C. for 4 h.
  • the reaction solution was cooled to room temperature and then 60 mL of chloroform was added.
  • the two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt.
  • the presence of chloride anions was monitored by silver nitrate test.
  • a rotary evaporator removed the chloroform and a wax was obtained in 93% yield.
  • Benzalkonium chloride (0.001 mol) was dissolved in warm distilled water.
  • trans-Cinnamic acid (0.001 mol) was added to the benzalkonium solution.
  • the reaction solution was stirred at 90° C. for 4 hours.
  • the reaction solution was cooled to room temperature then 60 mL of chloroform was added.
  • the two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt.
  • the presence of chloride anions was monitored by silver nitrate test.
  • a rotary evaporator removed the chloroform and an orange viscous liquid was obtained in 90% yield.
  • Hexadecylpyridinium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring.
  • Sodium dihexylsulfosuccinate (Colawet MA-80 from Colonial Chemicals, South Pittsburg, Tenn.; 0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt.
  • Decyldimethylammonium bromide (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring.
  • Sodium dihexylsulfosuccinate (Colawet MA-80 from Colonial Chemicals, South Pittsburg, Tenn.; 0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt.
  • Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring.
  • Sodium dihexylsulfosuccinate (Colawet MA-80 from Colonial Chemicals, South Pittsburg, Tenn.; 0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride anions was monitored by silver nitrate test.
  • Didecyldimethylammonium bromide (0.003 mol) was dissolved in 100 mL of distilled water by gentle heating and stirring.
  • Hexadecylpyridinium chloride (0.003 mol) was dissolved in 100 mL of distilled water by gentle heating and stirring.
  • Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of distilled water by gentle heating and stirring.
  • Hexadecylpyridinium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring.
  • Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring.
  • Didecyldimethylammonium bromide (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring.
  • Potassium penicillin G (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring.
  • the two solutions were combined and the reaction mixture was heated and stirred for 30 minutes.
  • the reaction mixture cooled to room temperature and then 60 mL of chloroform was added.
  • the reaction mixture was stirred for an additional 30 minutes.
  • the two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt.
  • the presence of chloride anions was monitored by silver nitrate test.
  • a rotary evaporator removed the chloroform and an orange gel was obtained in 76% yield.
  • Hexadecylpyridinium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring.
  • Potassium penicillin G (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring.
  • the two solutions were combined and the reaction mixture was heated and stirred for 30 minutes.
  • the reaction mixture cooled to room temperature and then 60 mL of chloroform was added.
  • the reaction mixture was stirred for an additional 30 minutes.
  • the two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt.
  • the presence of chloride anions was monitored by silver nitrate test.
  • Didecyldimethylammonium chloride (0.03 mol) was dissolved in 50 mL distilled water and sodium salicylate (0.04 mol) was added to solution. The mixture was stirred at 40° C. i for 1 h. After cooling to room temperature, 60 mL of chloroform was added. The chloroform phase was separated and washed with distilled water until chloride ions were no longer detected using AgNO 3 . The didecyldimethylammonium salicylate was obtained in 95% yield. The product is insoluble in water and was dried under vacuum.
  • the stechiometric amounts of didecyldimethylammonium saccharinate and sodium salicylate were mixed in distilled water and stirred at 60° C. for 2 h. After that time the solution was cooled to room temperature. The product was extracted from the aqueous solution with chloroform. The chloroform phase was removed and solvent was evaporated. Synthesized didecyldimethylammonium salicylate (90% yield) was dried under vacuum.
  • Benzalkonium saccharinate (0.01 mol) and benzoic acid (0.01 mol) were dissolved in 25 mL of hot acetone. The mixture was stirred at room temperature for 5 h. Distilled water was added. The organic phase was separated and washed with distilled water. Organic phase was evaporated and the product, benzalkonium salicylate, was dried under vacuum. 1 H and 13 C NMR (DMSO) were obtained.
  • Didecyldimethylammonium chloride (0.03 mol) was dissolved in 40 mL distilled water and diclofenac sodium salt (0.04 mol) was added to the solution. The solution was stirred at room temperature for 30 min. Chloroform (40 mL) was added to the reaction mixture and the mixture was stirred. After separation of the phases, the organic phase was washed with 40 mL distilled, cold water until chloride ions were no longer detected using AgNO 3 . Chloroform was removed and the residue was dried at 50° C. in vacuum.
  • Didecyldimethylammonium chloride (0.025 mol) was dissolved in 40 mL distilled water and the folic acid sodium salt (0.01 mol) was added. The solution was stirred at room temperature for 30 min. After separation of the phases, the organic phase was washed with distilled, cold water until chloride ions were no longer detected using AgNO 3 . The organic phase was separated and solvent was evaporated. The product (90% yield), didecyldimethylammonium N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoy]-L-glutamate, was dried at 50° C. under vacuum.
  • Lidocaine hydrochloride (0.0188 mol) was dissolved in 50 mL methanol and sodium docusate [bis(2-ethylhexyl)sulfosuccinate sodium salt] (0.0188 mol) was dissolved in 50 mL. The two solutions were combined and stirred for two hours, during this time a white precipitate (NaCl) formed. The methanol was removed by rotary evaporation which leaves a white sticky solid. To this solid, 150 mL of chloroform was added. A portion of the product dissolved the chloroform while the byproduct (NaCl) remained as a suspended solid. The NaCl was removed by filitration, and the solvent was removed by rotary evaporation. The product, lidocaine docusate, is a colorless syrup and is dried under high vacuum. 1 H and 13 C NMR (CDCl 3 ) were obtained.
  • Didecyldimethylammonium chloride (0.02 mol) was dissolved in distilled water and 0.015 mol of benzoic acid sodium salt was added. The solution was stirred at 80° C. for 7 h. The reaction mixture was extracted by chloroform. Chloroform phase was removed and washed with distilled, cold water until chloride ions were no longer detected using AgNO 3 . Then chloroform was removed. Obtainede benzoate in 85% yield was dried in vacuum. 1 H NMR and 13 C NMR (CDCl 3 ) were obtained.
  • Multicomponent ionic liquids containing 3 or more different ions were prepared to show the tenability of the disclosed compositions and methods. Three ionic liquids were prepared
  • the ionic liquids were prepared by dissolving each compound in a common solvent such as water, methanol, or ethanol. The solutions were combined and stirred. The solvent was then evaporated to reveal the ionic liquid and the inorganic salt. The ionic liquid was purified by dissolving it in a solvent, such as hexane, methanol, or ethanol. The inorganic salt was fitered off. The solvent was evaporated to produce the pure ionic liquid.
  • Emulsification of the two phases was quite pronounced, so each time the system was heated to about 60 ° C., then allowed to cool and settle for 5-7 days, after which point the dark chloroform phase was separated, dried over anhydrous MgSO 4 , filtered, and rotary evaporated to yield a viscous, deep brown-orange oil (Ranitidine docusate).
  • the two ions have known histamine H2-receptor antagonist and an emollient properties, respectively.
  • the mass was extracted with a chloroform-acetonitrile mixture, into which much of the material dissolved but some white solid (presumed to be NaNO 3 ) did not.
  • the mixture was filtered and evaporated under reduced pressure to give a soft mass of slightly off-white final product (which should be stored away from light because it is photosensitive).
  • This material was soluble in lidocaine docusate, some organic solvents, and was relatively slow to dissolve in water, doing so to only a limited degree.
  • the two ions have known antimicrobial and emollient properties, respectively.
  • Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of distilled water by gentle stirring and heating. Sulfathiazole sodium (0.003 mol) was dissolved in 60 mL of distilled water by gentle stirring and heating. The two solutions were combined and the reaction mixture was stirred and heated for 1 h. The reaction mixture was cooled to room temperature and 60 mL of chloroform was added to the reaction mixture. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride ions was monitored by silver nitrate test. A rotary evaporator removed the chloroform and an orange wax was obtained in a 50.04% yield.
  • Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of 95% ethanol by gentle stirring and heating.
  • Docusate sodium (0.003 mol) was dissolved in 100 mL of 95% ethanol by gentle stirring and heating. The two solutions were combined and the reaction mixture was stirred at room temperature for 1 h.
  • a rotary evaporator was used to remove the 95% ethanol and produced the ionic liquid and NaCl salt.
  • Hexane was used to dissolve the ionic liquid while the NaCl salt precipitated.
  • the NaCl salt was filtered from the reaction solution.
  • a rotary evaporator was used to remove the hexane and a white solid was obtained in a 78.32% yield.
  • the two ions have known antibacterial and emollient properties, respectively.
  • Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of 95% ethanol by gentle stirring and heating.
  • Thimerosal sodium (0.003 mol) was dissolved in 100 mL of 95% ethanol by gentle stirring and heating. The two solutions were combined and the reaction mixture was stirred at room temperature for 1 h.
  • a rotary evaporator was used to remove the 95% ethanol and produced the ionic liquid and NaCl salt.
  • Chloroform was used to dissolve the ionic liquid while the NaCl salt precipitated.
  • the NaCl salt was filtered from the reaction solution.
  • the benzalkonium ion has known antibacterial properties and the thimerosal ion is a known preservative in vaccines, ophthalmic and nasal products, and tattoo inks.
  • Hexadecylpyridinium chloride (0.003 mol) was dissolved in 100 mL of distilled water by gentle stirring and heating.
  • Valproic acid sodium salt (0.003 mol) was dissolved in 60 mL of distilled water by gentle stirring and heating. The two solutions were combined and the reaction mixture was stirred at room temperature for 1 h.
  • a rotary evaporator was used to remove the 95% ethanol and produced the ionic liquid and NaCl salt.
  • Tetrahydrofuran (THF) was used to dissolve the ionic liquid while the NaCl salt precipitated.
  • the NaCl salt was filtered from the reaction solution.
  • the two ions are used as an antibacterial and an anti-convulsant and mood stabilizer in bipolar disorder, respectively.
  • Hexadecylpyridinium chloride (0.003 mol) was dissolved in 100 mL of distilled water by gentle stirring and heating.
  • Sulfathiazole sodium (0.003 mol) was dissolved in 60 mL of distilled water by gentle stirring and heating. The two solutions were combined and the reaction mixture was stirred at room temperature for 1 h.
  • a rotary evaporator was used to remove the distilled water and produced the ionic liquid and NaCl salt. Benzene was used to dissolve the ionic liquid while the NaCl salt precipitated. The NaCl salt was filtered from the reaction solution.
  • a rotary evaporator was used to remove the benzene and a yellow solid was obtained in a 77.22% yield.
  • Mepenzolate bromide (0.003 mol) was dissolved in 100 mL 99% methanol by gentle stirring and heating.
  • Docusate sodium (0.003 mol) was dissolved in 60 mL 99% methanol by gentle stirring and heating. The two solutions were combined and the reaction mixture was stirred at room temperature for 1 h.
  • a rotary evaporator was used to remove the 99% methanol and produced the ionic liquid and NaBr salt. Hexane was used to dissolve the ionic liquid while the NaBr salt precipitated. The NaBr salt was filtered from the reaction solution.
  • Benzalkonium chloride (0.0015 mol) was dissolved in 100 mL 95% ethanol by gentle stirring and heating.
  • Mepenzolate bromide (0.003 mol) was dissolved in 100 mL 99% methanol by gentle stirring and heating.
  • Docusate sodium (0.003 mol) was dissolved in 60 mL 95% ethanol by gentle stirring and heating. The three solutions were combined and the reaction mixture was stirred at room temperature for 2 h. A rotary evaporator was used to remove the 95% ethanol and the 99% methanol. It produced the ionic liquid and NaBr and NaCl salt. Hexane was used to dissolve the ionic liquid while the NaBr and NaCl salt precipitated.
  • the NaBr and NaCl salt was filtered from the reaction solution.
  • a rotary evaporator was used to remove the hexane and a clear viscous liquid was obtained in a 44.09% yield.
  • Melting point (hot plate apparatus) liquid at room temperature.
  • the three ions have known antibacterial, anticholinergic, and emollient properties.
  • Benzalkonium chloride (0.002 mol) was dissolved in 100 mL 95% ethanol by gentle stirring and heating.
  • Mepenzolate bromide (0.001 mol) was dissolved in 100 mL 99% methanol by gentle stirring and heating.
  • Docusate sodium (0.003 mol) was dissolved in 60 mL 95% ethanol by gentle stirring and heating. The three solutions were combined and the reaction mixture was stirred at room temperature for 2 h. A rotary evaporator was used to remove the 95% ethanol and the 99% methanol. It produced the ionic liquid and NaBr and NaCl salt. Hexane was used to dissolve the ionic liquid while the NaBr and NaCl salt precipitated.
  • the NaBr and NaCl salt was filtered from the reaction solution.
  • a rotary evaporator was used to remove the hexane and a whitish gel was obtained in a 68.84% yield.
  • Melting point (hot plate apparatus) liquid at room temperature.
  • Benzalkonium chloride (0.001 mol) was dissolved in 100 mL 95% ethanol by gentle stirring and heating.
  • Mepenzolate bromide (0.002 mol) was dissolved in 100 mL 99% methanol by gentle stirring and heating.
  • Docusate sodium (0.003 mol) was dissolved in 60 mL 95% ethanol by gentle stirring and heating. The three solutions were combined and the reaction mixture was stirred at room temperature for 2 h.
  • a rotary evaporator was used to remove the 95% ethanol and the 99% methanol. It produced the ionic liquid and NaBr and NaCl salt.
  • Hexane was used to dissolve the ionic liquid while the NaBr and NaCl salt precipitated.
  • the NaBr and NaCl salt was filtered from the reaction solution.
  • Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of distilled water by gentle stirring and heating.
  • Sulfathiazole sodium (0.0015 mol) was dissolved in 50 mL of distilled water by gentle stirring and heating.
  • Acesulfamate potassium (0.0015 mol) was dissolved in 50 mL of distilled water by gentle stirring and heating.
  • the three solutions were combined and the reaction mixture was stirred and heated for 1 h.
  • a rotary evaporator was used to remove the distilled water. It produced the ionic liquid and NaCl salt. 99% methanol was used to dissolve the ionic liquid while the NaCl salt precipitated.
  • the NaCl salt was filtered from the reaction solution.
  • Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of distilled water by gentle stirring and heating. Saccharinate sodium (0.0015 mol) was dissolved in 50 mL of distilled water by gentle stirring and heating. Acesulfamate potassium (0.0015 mol) was dissolved in 50 mL of distilled water by gentle stirring and heating. The three solutions were combined and the reaction mixture was stirred and heated for 1 h. A rotary evaporator was used to remove the distilled water. It produced the ionic liquid and NaCl and KCl salt. 95% ethanol was used to dissolve the ionic liquid while the NaCl and KCl salt precipitated. The NaCl and KCl salt was filtered from the reaction solution.
  • Hexadecylpyridinium chloride (0.003 mol) was dissolved in 100 mL of distilled water by gentle stirring and heating. Saccharinate sodium (0.0015 mol) was dissolved in 50 mL of distilled water by gentle stirring and heating. Acesulfamate potassium (0.0015 mol) was dissolved in 50 mL of distilled water by gentle stirring and heating. The three solutions were combined and the reaction mixture was stirred and heated for 1 h. A rotary evaporator was used to remove the distilled water. It produced the ionic liquid and KCl and NaCl salt. 99% methanol was used to dissolve the ionic liquid while the KCl and NaCl salt precipitated. The KCl and NaCl salt was filtered from the reaction solution.
  • Diundecyldimethlammonium bromide (0.0023 mol) was dissolved in 7 mL of distilled water by gentle heating and stirring.
  • Sodium saccharinate (0.001 mol) was dissolved in 7 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 90 minutes. The reaction mixture was cooled to room temperature and then 7 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of bromide anions was monitored by silver nitrate test.
  • Diundecyldimethlammonium bromide (0.0023 mol) was dissolved in 7 mL of distilled water by gentle heating and stirring.
  • Potassium acesulfamate (0.001 mol) was dissolved in 7 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 90 minutes. The reaction mixture was cooled to room temperature and then 7 mL of chloroform was added. The reaction mixture was stirred for an additional 20 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of bromide anions was monitored by silver nitrate test.
  • Didecyldimethylammonium bromide (0.005 mol) was dissolved 100 mL of 95% ethanol by gentle stirring.
  • Docusate sodium was dissolved in 50 mL of 95% ethanol by gentle stirring.
  • the two solutions were combined and the reaction mixture was stirred for 1 hour at room temperature.
  • a rotary evaporator removed the ethanol to give the ionic liquid and NaBr.
  • the ionic liquid was dissolved in hexane and the NaBr was filtered off.
  • a rotary evaporator removed the hexane to give a white solid obtained in a 78.00% yield.
  • the rat tail flick test is used to determine the local anesthetic ability of lidocaine docusate compared with lidocaine hydrochloride.
  • the rat is immobilized in a restraining sock, so that the tail is only exposed.
  • the tail is dipped into hot water and the number of times the rat flicks its tail is recorded.
  • the rat's tail should be numb therefore it will not feel the hot water and the number of tail flicks should decrease.
  • FIGS. 4A and B are two graphs with the results at concentrations of DMSO lidocaine hydrochloride solution and lidocaine docusate of 1 mM and 100 mM.
  • lidocaine docusate has a higher and longer anesthetic ability than lidocaine hydrochloride in DMSO. This is likely due to the synergistic effects.
  • Hexadecylpyridinium Clofencet Fluroxypyr, Diflufenzopyr, Mesosulfuron, Probexadione, Pantoprazole, Risedronate, Losartan, Rabeprazole, Fosinopril, Ceftioxone, Atorvastatin, Pravastatin, Alendronate, Montelukast, Tazobactam, Allura Red AC, Tartrazine, Indigotine, Erythrosine, and Sunset Yellow
  • Hexadecylpyridinium chloride (0.001 mol) is dissolved in 60 mL of distilled water by gentle heating and stirring.
  • the anion (0.001 mol) is dissolved in 60 mL of distilled water by gentle heating and stirring.
  • the two solutions are combined and the reaction mixture is heated and stirred for 30 minutes.
  • the reaction mixture is cooled to room temperature and then 60 mL of chloroform is added.
  • the reaction mixture is stirred for an additional 30 minutes.
  • the two phases are separated and the chloroform phase is washed several times with cool distilled water to remove any inorganic salt.
  • the presence of chloride anions is monitored by silver nitrate test.
  • a rotary evaporator is used to remove the chloroform and a product will be obtained.
  • Hot plate apparatus can be used to determine melting point and percent yield of the compound can be calculated. Also 1 H and 13 C NMR and thermalgravimetric analysis can be performed.
  • Benzalkonium Clofencet Fluroxypyr, Diflufenzopyr, Mesosulfuron, Prohexadione, Pantoprazole, Risedronate, Losartan, Rabeprazole, Fosinopril, Ceftioxone, Atorvastatin, Pravastatin, Alendronate, Montelukast, Tazobactam, Allura Red AC, Tartrazine, Indigotine, Erythrosine, and Sunset Yellow
  • Benzalkonium chloride (0.001 mol) is dissolved in 60 mL of distilled water by gentle heating and stirring.
  • the anion (0.001 mol) is dissolved in 60 mL of distilled water by gentle heating and stirring.
  • the two solutions are combined and the reaction mixture is heated and stirred for 30 minutes.
  • the reaction mixture is cooled to room temperature and then 60 mL of chloroform is added.
  • the reaction mixture is stirred for an additional 30 minutes.
  • the two phases are separated and the chloroform phase is washed several times with cool distilled water to remove any inorganic salt.
  • the presence of chloride anions is monitored by silver nitrate test.
  • a rotary evaporator is used to remove the chloroform and a product will be obtained.
  • Hot plate apparatus can be used to determine melting point and percent yield of the compound can be calculated. Also 1 H and 13 C NMR and thermalgravimetric analysis can be performed.

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